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  • 1.
    Asp, Julia
    et al.
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Jonsson, Marianne
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dellgren, Goran
    Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Comparison of human cardiac gene expression profiles in paired samples of right atrium and left ventricle collected in vivo2012Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, nr 1, s. 89-98Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies of expressed genes in human heart provide insight into both physiological and pathophysiological mechanisms. This is of importance for extended understanding of cardiac function as well as development of new therapeutic drugs. Heart tissue for gene expression studies is generally hard to obtain, particularly from the ventricles. Since different parts of the heart have different functions, expression profiles should likely differ between these parts. The aim of the study was therefore to compare the global gene expression in cardiac tissue from the more accessible auricula of the right atrium to expression in tissue from the left ventricle. Tissue samples were collected from five men undergoing aortic valve replacement or coronary artery bypass grafting. Global gene expression analysis identified 542 genes as differentially expressed between the samples extracted from these two locations, corresponding to similar to 2% of the genes covered by the microarray; 416 genes were identified as abundantly expressed in right atrium, and 126 genes were abundantly expressed in left ventricle. Further analysis of the differentially expressed genes according to available annotations, information from curated pathways and known protein interactions, showed that genes with higher expression in the ventricle were mainly associated with contractile work of the heart. Transcription in biopsies from the auricula of the right atrium on the other hand indicated a wider area of functions, including immunity and defense. In conclusion, our results suggest that biopsies from the auricula of the right atrium may be suitable for various genetic studies, but not studies directly related to muscle work.

  • 2.
    Asplund, Annika
    et al.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Küppers-Munther, Barbara
    Takara Bio Europe AB, Gothenburg, Sweden.
    A novel maintenance medium extends the life-span and enables long term applications for both human primary hepatocytes and human pluripotent stem cell derived hepatocytes in conventional 2D cultures2017Konferansepaper (Fagfellevurdert)
  • 3.
    Correia, Cláudia
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Wang, Qing-Dong
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Linhardt, Gunilla
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Carlsson, Leif G.
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Walentinsson, Anna
    Translational Science & Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Rydén-Markinhutha, Katarina
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Behrendt, Margareta
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Wikström, Johannes
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Late-Stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Jennbacken, Karin
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Unraveling the Metabolic Derangements Occurring in Non-infarcted Areas of Pig Hearts With Chronic Heart Failure2021Inngår i: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 8, artikkel-id 753470Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: After myocardial infarction (MI), the non-infarcted left ventricle (LV) ensures appropriate contractile function of the heart. Metabolic disturbance in this region greatly exacerbates post-MI heart failure (HF) pathology. This study aimed to provide a comprehensive understanding of the metabolic derangements occurring in the non-infarcted LV that could trigger cardiovascular deterioration. Methods and Results: We used a pig model that progressed into chronic HF over 3 months following MI induction. Integrated gene and metabolite signatures revealed region-specific perturbations in amino acid- and lipid metabolism, insulin signaling and, oxidative stress response. Remote LV, in particular, showed impaired glutamine and arginine metabolism, altered synthesis of lipids, glucose metabolism disorder, and increased insulin resistance. LPIN1, PPP1R3C, PTPN1, CREM, and NR0B2 were identified as the main effectors in metabolism dysregulation in the remote zone and were found differentially expressed also in the myocardium of patients with ischemic and/or dilated cardiomyopathy. In addition, a simultaneous significant decrease in arginine levels and altered PRCP, PTPN1, and ARF6 expression suggest alterations in vascular function in remote area. Conclusions: This study unravels an array of dysregulated genes and metabolites putatively involved in maladaptive metabolic and vascular remodeling in the non-infarcted myocardium and may contribute to the development of more precise therapies to mitigate progression of chronic HF post-MI.

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  • 4.
    de Peppo, G.M.
    et al.
    Sahlgrenska Academy at University of Gothenburg.
    Svensson, S.
    Sahlgrenska Academy at University of Gothenburg.
    Lennerås, M.
    BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Göteborg.
    Synnergren, Jane
    Högskolan i Skövde, Forskningscentrum för Systembiologi. Högskolan i Skövde, Institutionen för vård och natur.
    Stenberg, J.
    Sahlgrenska University Hospital, University of Gothenburg.
    Strehl, R.
    Cellartis AB, Göteborg.
    Hyllner, J.
    Cellartis AB, Göteborg.
    Thomsen, P.
    Sahlgrenska Academy at University of Gothenburg.
    Karlsson, C.
    Sahlgrenska Academy at University of Gothenburg.
    Human Embryonic Mesodermal Progenitors Highly Resemble Human Mesenchymal Stem Cells and Display High Potential for Tissue Engineering Applications2010Inngår i: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 16, nr 7, s. 2161-2182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adult stem cells, such as human mesenchymal stem cells (hMSCs), show limited proliferative capacity and, after long-term culture, lose their differentiation capacity and are therefore not an optimal cell source for tissue engineering. Human embryonic stem cells (hESCs) constitute an important new resource in this field, but one major drawback is the risk of tumor formation in the recipients. One alternative is to use progenitor cells derived from hESCs which are more lineage restricted but do not form teratomas. We have recently derived a cell line from hESCs denoted human embryonic stem cell-derived mesodermal progenitors (hESMPs) and here, using genome wide microarray analysis, report that the process of hES-MPs derivation results in a significantly altered expression of hESCs characteristic genes to an expression level highly similar to that of hMSCs. However, hES-MPs displayed a significantly higher proliferative capacity and longer telomeres. Interestingly, the hES-MPs also demonstrated a lower expression of HLA class II proteins before and after interferon-γ treatment, indicating that these cells may somewhat be immunoprivileged and potentially used for HLA-incompatible transplantation. The hES-MPs are thus an appealing alternative to hMSCs in tissue engineering applications and stem cell-based therapies for mesodermal tissues.

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  • 5.
    Delsing, Louise
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology, Gothenburg, Sweden / Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Dönnes, Pierre
    SciCross AB, Skövde, Sweden.
    Sánchez, José
    Biostatistics, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Clausen, Maryam
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Voulgaris, Dmitrios
    Department of Micro and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm.
    Herland, Anna
    Department of Micro and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Zetterberg, Henrik
    Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology, Gothenburg, Sweden / iClinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom / UK Dementia Research Institute at UCL, London, United Kingdom.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Barrier properties and transcriptome expression in human iPSC-derived models of the blood-brain barrier2018Inngår i: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 36, nr 12, s. 1816-1827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cell-based models of the blood-brain barrier (BBB) are important for increasing the knowledge of BBB formation, degradation and brain exposure of drug substances. Human models are preferred over animal models because of inter-species differences in BBB structure and function. However, access to human primary BBB tissue is limited and has shown degeneration of BBB functions in vitro. Human induced pluripotent stem cells (iPSCs) can be used to generate relevant cell types to model the BBB with human tissue. We generated a human iPSC-derived model of the BBB that includes endothelial cells in co-culture with pericytes, astrocytes and neurons. Evaluation of barrier properties showed that the endothelial cells in our co-culture model have high transendothelial electrical resistance, functional efflux and ability to discriminate between CNS permeable and non-permeable substances. Whole genome expression profiling revealed transcriptional changes that occur in co-culture, including upregulation of tight junction proteins such as claudins and neurotransmitter transporters. Pathway analysis implicated changes in the WNT, TNF and PI3K-Akt pathways upon co-culture. Our data suggests that co-culture of iPSC-derived endothelial cells promotes barrier formation on a functional and transcriptional level. The information about gene expression changes in co-culture can be used to further improve iPSC-derived BBB models through selective pathway manipulation.

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  • 6.
    Delsing, Louise
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Institute of Neuroscience and Physiology, Department of Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Sweden / Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Mölndal, Sweden.
    Herland, Anna
    Division of Micro and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden / AIMES, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hicks, Ryan
    Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom / UK Dementia Research Institute at UCL, London, United Kingdom.
    Models of the blood-brain barrier using iPSC-derived cells2020Inngår i: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 107, artikkel-id 103533Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The blood-brain barrier (BBB) constitutes the interface between the blood and the brain tissue. Its primary function is to maintain the tightly controlled microenvironment of the brain. Models of the BBB are useful for studying the development and maintenance of the BBB as well as diseases affecting it. Furthermore, BBB models are important tools in drug development and support the evaluation of the brain-penetrating properties of novel drug molecules. Currently used in vitro models of the BBB include immortalized brain endothelial cell lines and primary brain endothelial cells of human and animal origin. Unfortunately, many cell lines and primary cells do not recreate physiological restriction of transport in vitro. Human-induced pluripotent stem cell (iPSC)-derived brain endothelial cells have proven a promising alternative source of brain endothelial-like cells that replicate tight cell layers with low paracellular permeability. Given the possibility to generate large amounts of human iPSC-derived brain endothelial cells they are a feasible alternative when modelling the BBB in vitro. iPSC-derived brain endothelial cells form tight cell layers in vitro and their barrier properties can be enhanced through coculture with other cell types of the BBB. Currently, many different models of the BBB using iPSC-derived cells are under evaluation to study BBB formation, maintenance, disruption, drug transport and diseases affecting the BBB. This review summarizes important functions of the BBB and current efforts to create iPSC-derived BBB models in both static and dynamic conditions. In addition, it highlights key model requirements and remaining challenges for human iPSC-derived BBB models in vitro.

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  • 7.
    Delsing, Louise
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden / Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Mölndal, Sweden.
    Kallur, Therese
    BioLamina, Sundbyberg, Sweden.
    Zetterberg, Henrik
    Department of Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK / UK Dementia Research Institute at UCL, London, UK.
    Hicks, Ryan
    Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Enhanced xeno-free differentiation of hiPSC-derived astroglia applied in a blood-brain barrier model2019Inngår i: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 16, nr 1, artikkel-id 27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Human induced pluripotent stem cells (hiPSC) hold great promise for use in cell therapy applications and for improved in vitro models of human disease. So far, most hiPSC differentiation protocols to astroglia use undefined, animal-containing culture matrices. Laminins, which play an essential role in the regulation of cell behavior, offer a source of defined, animal-free culture matrix. Methods In order to understand how laminins affect astroglia differentiation, recombinant human laminin-521 (LN521), was compared to a murine Engelbreth-Holm-Swarm sarcoma derived laminin (L2020). Astroglia expression of protein and mRNA together with glutamate uptake and protein secretion function, were evaluated. Finally, these astroglia were evaluated in a coculture model of the blood-brain barrier (BBB). Results Astroglia of good quality were generated from hiPSC on both LN521 and L2020. However, astroglia differentiated on human LN521 showed higher expression of several astroglia specific mRNAs and proteins such as GFAP, S100B, Angiopoietin-1, and EAAT1, compared to astroglia differentiated on murine L2020. In addition, glutamate uptake and ability to induce expression of junction proteins in endothelial cells were affected by the culture matrix for differentiation. Conclusion Our results suggest that astroglia differentiated on LN521 display an improved phenotype and are suitable for coculture in a hiPSC-derived BBB model. This provides a starting point for a more defined and robust derivation of astroglia for use in BBB coculture models.

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  • 8.
    Delsing, Louise
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Hicks, Ryan
    IMED Discovery Sciences, AstraZeneca, Mölndal, Sweden.
    Zetterberg, Henrik
    University of Gothenburg, Gothenburg, Sweden.
    Human iPSC-derived endothelial cells can develop in to brain-like endothelial cells after coculture with primary human brain cells2017Konferansepaper (Fagfellevurdert)
  • 9.
    Ghosheh, Nidal
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Küppers-Munther, Barbara
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, Annika
    Takara Bio Europe AB, Gothenburg, Sweden.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Björquist, Petter
    VeriGraft AB, Gothenburg, Sweden.
    Andersson, Tommy B.
    Cardiovascular Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden / Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Carén, Helena
    Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Simonsson, Stina
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Late Stage Cardiovascular, Renal, and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Human Pluripotent Stem Cell-Derived Hepatocytes Show Higher Transcriptional Correlation with Adult Liver Tissue than with Fetal Liver Tissue2020Inngår i: ACS Omega, E-ISSN 2470-1343, Vol. 5, nr 10, s. 4816-4827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human pluripotent stem cell-derived hepatocytes (hPSC-HEP) display many properties of mature hepatocytes, including expression of important genes of the drug metabolizing machinery, glycogen storage, and production of multiple serum proteins. To this date, hPSC-HEP do not, however, fully recapitulate the complete functionality of in vivo mature hepatocytes. In this study, we applied versatile bioinformatic algorithms, including functional annotation and pathway enrichment analyses, transcription factor binding-site enrichment, and similarity and correlation analyses, to datasets collected from different stages during hPSC-HEP differentiation and compared these to developmental stages and tissues from fetal and adult human liver. Our results demonstrate a high level of similarity between the in vitro differentiation of hPSC-HEP and in vivo hepatogenesis. Importantly, the transcriptional correlation of hPSC-HEP with adult liver (AL) tissues was higher than with fetal liver (FL) tissues (0.83 and 0.70, respectively). Functional data revealed mature features of hPSC-HEP including cytochrome P450 enzymes activities and albumin secretion. Moreover, hPSC-HEP showed expression of many genes involved in drug absorption, distribution, metabolism, and excretion. Despite the high similarities observed, we identified differences of specific pathways and regulatory players by analyzing the gene expression between hPSC-HEP and AL. These findings will aid future intervention and improvement of in vitro hepatocyte differentiation protocol in order to generate hepatocytes displaying the complete functionality of mature hepatocytes. Finally, on the transcriptional level, our results show stronger correlation and higher similarity of hPSC-HEP to AL than to FL. In addition, potential targets for further functional improvement of hPSC-HEP were also identified. 

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  • 10.
    Ghosheh, Nidal
    et al.
    Högskolan i Skövde, Forskningscentrum för Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap. Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Küppers-Munther, Barbara
    Takara Bio Europe Aktiebolaget, Gothenburg, Sweden.
    Asplund, Annika
    Takara Bio Europe Aktiebolaget, Gothenburg, Sweden.
    Edsbagge, Josefina
    Takara Bio Europe Aktiebolaget, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Andersson, Tommy B.
    Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden / Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Björquist, Petter
    NovaHep Aktiebolaget, Gothenburg, Sweden.
    Andersson, Christian X.
    Takara Bio Europe Aktiebolaget, Gothenburg, Sweden.
    Carén, Helena
    Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simonsson, Stina
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca Research and Development, Global Medicines Development Cardiovascular and Metabolic Diseases Global Medicines Development Unit, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue2017Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 49, nr 8, s. 430-446Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatocytes derived from human pluripotent stem cells (hPSC-HEP) have the potential to replace presently used hepatocyte sources applied in liver disease treatment and models of drug discovery and development. Established hepatocyte differentiation protocols are effective and generate hepatocytes, which recapitulate some key features of their in vivo counterparts. However, generating mature hPSC-HEP remains a challenge. In this study, we applied transcriptomics to investigate the progress of in vitro hepatic differentiation of hPSCs at the developmental stages, definitive endoderm, hepatoblasts, early hPSC-HEP, and mature hPSC-HEP, to identify functional targets that enhance efficient hepatocyte differentiation. Using functional annotation, pathway and protein interaction network analyses, we observed the grouping of differentially expressed genes in specific clusters representing typical developmental stages of hepatic differentiation. In addition, we identified hub proteins and modules that were involved in the cell cycle process at early differentiation stages. We also identified hub proteins that differed in expression levels between hPSC-HEP and the liver tissue controls. Moreover, we identified a module of genes that were expressed at higher levels in the liver tissue samples than in the hPSC-HEP. Considering that hub proteins and modules generally are essential and have important roles in the protein-protein interactions, further investigation of these genes and their regulators may contribute to a better understanding of the differentiation process. This may suggest novel target pathways and molecules for improvement of hPSC-HEP functionality, having the potential to finally bring this technology to a wider use.

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    Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue
  • 11.
    Ghosheh, Nidal
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Olsson, Björn
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Edsbagge, Josefina
    Takara Bio Europe AB, Gothenburg, Sweden.
    Küppers-Munther, Barbara
    Takara Bio Europe AB, Gothenburg, Sweden.
    Van Giezen, Mariska
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, Annika
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Andersson, Tommy B.
    AstraZeneca R&D, CVMD DMPK, Mölndal, Sweden / Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Björquist, Petter
    NovaHep AB, Gothenburg, Sweden.
    Carén, Helena
    Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simonsson, Stina
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines2016Inngår i: Stem Cells International, ISSN 1687-9678, Vol. 2016, artikkel-id 8648356Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human pluripotent stem cells- (hPSCs-) derived hepatocytes have the potential to replace many hepatic models in drug discovery and provide a cell source for regenerative medicine applications. However, the generation of fully functional hPSC-derived hepatocytes is still a challenge. Towards gaining better understanding of the differentiation and maturation process, we employed a standardized protocol to differentiate six hPSC lines into hepatocytes and investigated the synchronicity of the hPSC lines by applying RT-qPCR to assess the expression of lineage-specific genes (OCT4, NANOG, T, SOX17, CXCR4, CER1, HHEX, TBX3, PROX1, HNF6, AFP, HNF4a, KRT18, ALB, AAT, and CYP3A4) which serve as markers for different stages during liver development. The data was evaluated using correlation and clustering analysis, demonstrating that the expression of these markers is highly synchronized and correlated well across all cell lines. The analysis also revealed a distribution of the markers in groups reflecting the developmental stages of hepatocytes. Functional analysis of the differentiated cells further confirmed their hepatic phenotype. Taken together, these results demonstrate, on the molecular level, the highly synchronized differentiation pattern across multiple hPSC lines. Moreover, this study provides additional understanding for future efforts to improve the functionality of hPSC-derived hepatocytes and thereby increase the value of related models.

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  • 12.
    Godoy, Patricio
    et al.
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany / Department of Physiology, Faculty of Biological Sciences, University of Concepción, Chile.
    Schmidt-Heck, Wolfgang
    Leibniz Institute for Natural Product Research and Infection Biology eV-Hans-Knöll Institute, Jena, Germany.
    Natarajan, Karthick
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Lucendo-Villarin, Baltasar
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Szkolnicka, Dagmara
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Asplund, Annika
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Björquist, Petter
    NovaHep AB, Gothenburg, Sweden.
    Widera, Agata
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Stöber, Regina
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Campos, Gisela
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Hammad, Seddik
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Sachinidis, Agapios
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Chaudhari, Umesh
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Damm, Georg
    Charité University Medicine Berlin, Department of General-, Visceral- and Transplantation Surgery, Berlin, Germany.
    Weiss, Thomas S.
    Center for Liver Cell Research, Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, Regensburg, Germany.
    Nüssler, Andreas
    Eberhard Karls University Tübingen, BG Trauma Center, Siegfried Weller Institut, Tübingen, Germany.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Edlund, Karolina
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Küppers-Munther, Barbara
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Hay, David C.
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Hengstler, Jan G.
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells2015Inngår i: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 63, nr 4, s. 934-942Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND & AIMS: The differentiation of stem cells to hepatocyte-like cells (HLC) offers the perspective of unlimited supply of human hepatocytes. However, the degree of differentiation of HLC remains controversial. To obtain an unbiased characterization, we performed a transcriptomic study with HLC derived from human embryonic and induced stem cells (ESC, hiPSC) from three different laboratories.

    METHODS: Genome-wide gene expression profiles of ESC and HLC were compared to freshly isolated and up to 14days cultivated primary human hepatocytes. Gene networks representing successful and failed hepatocyte differentiation, and the transcription factors involved in their regulation were identified.

    RESULTS: Gene regulatory network analysis demonstrated that HLC represent a mixed cell type with features of liver, intestine, fibroblast and stem cells. The "unwanted" intestinal features were associated with KLF5 and CDX2 transcriptional networks. Cluster analysis identified highly correlated groups of genes associated with mature liver functions (n=1057) and downregulated proliferation associated genes (n=1562) that approach levels of primary hepatocytes. However, three further clusters containing 447, 101, and 505 genes failed to reach levels of hepatocytes. Key TF of two of these clusters include SOX11, FOXQ1, and YBX3. The third unsuccessful cluster, controlled by HNF1, CAR, FXR, and PXR, strongly overlaps with genes repressed in cultivated hepatocytes compared to freshly isolated hepatocytes, suggesting that current in vitro conditions lack stimuli required to maintain gene expression in hepatocytes, which consequently also explains a corresponding deficiency of HLC.

    CONCLUSIONS: The present gene regulatory network approach identifies key transcription factors which require modulation to improve HLC differentiation.

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  • 13.
    González-King, Hernán
    et al.
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Rodrigues, Patricia G.
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Albery, Tamsin
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Tangruksa, Benyapa
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Gurrapu, Ramya
    AstraZeneca India Private Limited, Neville Tower 11th Floor, Ramanujan IT SEZ, Rajv Gandhi Salai (OMR), Taramani, Tamil Nadu, Chennai, India.
    Silva, Andreia M.
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden ; Anjarium Biosciences AG, Schlieren, Switzerland.
    Musa, Gentian
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Kardasz, Dominika
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Liu, Kai
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden ; Pharmaceutical Sciences, Advanced Drug Delivery, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Kull, Bengt
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Åvall, Karin
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Rydén-Markinhuhta, Katarina
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Incitti, Tania
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Sharma, Nitin
    AstraZeneca India Private Limited, Neville Tower 11th Floor, Ramanujan IT SEZ, Rajv Gandhi Salai (OMR), Taramani, Tamil Nadu, Chennai, India.
    Graneli, Cecilia
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Valadi, Hadi
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Petkevicius, Kasparas
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Carracedo, Miguel
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Tejedor, Sandra
    Högskolan i Skövde, Forskningsmiljön Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap. Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Ivanova, Alena
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Chief Medical Office, Global Patient Safety, AstraZeneca, Mölndal, Sweden.
    Menasché, Phillipe
    Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, Université de Paris, PARCC, INSERM, Paris, France.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dekker, Niek
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Wang, Quing -Dong
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Jennbacken, Karin
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Head-to-head comparison of relevant cell sources of small extracellular vesicles for cardiac repair: Superiority of embryonic stem cells2024Inngår i: Journal of Extracellular Vesicles, E-ISSN 2001-3078, Vol. 13, nr 5, artikkel-id e12445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM-MSC), human immortalized MSC (hTERT-MSC), human embryonic stem cells (ESC), ESC-derived cardiac progenitor cells (CPC), human ESC-derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC-derived sEV (ESC-sEV) exhibited the best pro-angiogenic and anti-fibrotic effects in vitro. Then, we evaluated the functionality of the sEV with the most promising performances in vitro, in a murine model of MI-reperfusion injury (IRI) and analysed their RNA and protein compositions. In vivo, ESC-sEV provided the most favourable outcome after MI by reducing adverse cardiac remodelling through down-regulating fibrosis and increasing angiogenesis. Furthermore, transcriptomic, and proteomic characterizations of sEV derived from hTERT-MSC, ESC, and CPC revealed factors in ESC-sEV that potentially drove the observed functions. In conclusion, ESC-sEV holds great promise as a cell-free treatment for promoting cardiac repair following MI. 

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  • 14.
    Granéli, Cecilia
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Global Medicines Development, CVRM, AstraZeneca Gothenburg, Mölndal, Sweden.
    Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models2019Inngår i: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 15, nr 1, s. 13-22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The global burden of diabetes has drastically increased over the past decades and in 2017 approximately 4 million deaths were caused by diabetes and cardiovascular complications. Diabetic cardiomyopathy is a common complication of diabetes with early manifestations of diastolic dysfunction and left ventricular hypertrophy with subsequent progression to systolic dysfunction and ultimately heart failure. An in vitro model accurately recapitulating key processes of diabetic cardiomyopathy would provide a useful tool for investigations of underlying disease mechanisms to further our understanding of the disease and thereby potentially advance treatment strategies for patients. With their proliferative capacity and differentiation potential, human induced pluripotent stem cells (iPSCs) represent an appealing cell source for such a model system and cardiomyocytes derived from induced pluripotent stem cells have been used to establish other cardiovascular related disease models. Here we review recently made advances and discuss challenges still to be overcome with regard to diabetic cardiomyopathy models, with a special focus on iPSC-based systems. Recent publications as well as preliminary data presented here demonstrate the feasibility of generating cardiomyocytes with a diabetic phenotype, displaying insulin resistance, impaired calcium handling and hypertrophy. However, capturing the full metabolic- and functional phenotype of the diabetic cardiomyocyte remains to be accomplished. 

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  • 15.
    Holmgren, Gustav
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Ghosheh, Nidal
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Zeng, Xianmin
    Buck Institute for Research on Aging, Buck Institute, Novato, California, USA.
    Bogestål, Yalda
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca Research and Development, Global Medicines Development, Cardiovascular and Metabolic Diseases Global Medicines Development Unit, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Identification of stable reference genes in differentiating human pluripotent stem cells2015Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 47, nr 6, s. 232-239Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reference genes, often referred to as housekeeping genes (HKGs), are frequently used to normalize gene expression data based on the assumption that they are expressed at a constant level in the cells. However, several studies have shown that there may be a large variability in the gene expression levels of HKGs in various cell types. In a previous study, employing human embryonic stem cells (hESCs) subjected to spontaneous differentiation, we observed that the expression of commonly used HKG varied to a degree that rendered them inappropriate to use as reference genes under those experimental settings. Here we present a substantially extended study of the HKG signature in human pluripotent stem cells (hPSC), including nine global gene expression datasets from both hESC and human induced pluripotent stem cells (hiPSCs), obtained during directed differentiation towards endoderm-, mesoderm-, and ectoderm derivatives. Sets of stably expressed genes were compiled and a handful of genes (e.g., EID2, ZNF324B, CAPN10, and RABEP2) were identified as generally applicable reference genes in hPSCs across all cell lines and experimental conditions. The stability in gene expression profiles was confirmed by quantitative PCR (RT-qPCR) analysis. Taken together, the current results suggest that differentiating hPSCs have a distinct HKG signature, which in some aspects is different from somatic cell types, and underscore the necessity to validate the stability of reference genes under the actual experimental setup used. In addition, the novel putative HKGs identified in this study can preferentially be used for normalization of gene expression data obtained from differentiating hPSCs.

  • 16.
    Holmgren, Gustav
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Takara Bio Europe AB, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca Gothenburg, CVMD GMed, GMD, Mölndal, Sweden.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin - integration and visualization of multi omics data2018Inngår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 163, nr 1, s. 182-195Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anthracyclines, such as doxorubicin, are highly efficient chemotherapeutic agents against a variety of cancers. However, anthracyclines are also among the most cardiotoxic therapeutic drugs presently on the market. Chemotherapeutic-induced cardiomyopathy is one of the leading causes of disease and mortality in cancer survivors. The exact mechanisms responsible for doxorubicin-induced cardiomyopathy are not completely known, but the fact that the cardiotoxicity is dose-dependent and that there is a variation in time-to-onset of toxicity, and gender- and age differences suggests that several mechanisms may be involved.In the present study, we investigated doxorubicin-induced cardiotoxicity in human pluripotent stem cell-derived cardiomyocytes using proteomics. In addition, different sources of omics data (protein, mRNA, and microRNA) from the same experimental setup were further combined and analyzed using newly developed methods to identify differential expression in data of various origin and types. Subsequently, the results were integrated in order to generate a combined visualization of the findings.In our experimental model system, we exposed cardiomyocytes derived from human pluripotent stem cells to doxorubicin for up to two days, followed by a wash-out period of additionally 12 days. Besides an effect on the cell morphology and cardiomyocyte functionality, the data show a strong effect of doxorubicin on all molecular levels investigated. Differential expression patterns that show a linkage between the proteome, transcriptome, and the regulatory microRNA network, were identified. These findings help to increase the understanding of the mechanisms behind anthracycline-induced cardiotoxicity and suggest putative biomarkers for this condition.

  • 17.
    Holmgren, Gustav
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Sjögren, Anna-Karin
    Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca RandD, Mölndal, Sweden.
    Barragan, Isabel
    Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Sabirsh, Alan
    Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca RandD, Mölndal, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Cellectis AB, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Björquist, Petter
    NovaHep AB, Gothenburg, Sweden / Cellectis AB, Gothenburg, Sweden.
    Ingelman-Sundberg, Magnus
    Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Tommy B.
    Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden / Department of Drug Metabolism and Pharmacokinetics, AstraZeneca RandD, Mölndal, Sweden.
    Edsbagge, Josefina
    Cellectis AB, Gothenburg, Sweden.
    Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes2014Inngår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 42, nr 9, s. 1401-1406Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human pluripotent stem cells (hPSC) have the potential to become important tools for the establishment of new models for in vitro drug testing of, for example, toxicity and pharmacological effects. Late-stage attrition in the pharmaceutical industry is to a large extent caused by selection of drug candidates using nonpredictive preclinical models that are not clinically relevant. The current hepatic in vivo and in vitro models show clear limitations, especially for studies of chronic hepatotoxicity. For these reasons, we evaluated the potential of using hPSC-derived hepatocytes for long-term exposure to toxic drugs. The differentiated hepatocytes were incubated with hepatotoxic compounds for up to 14 days, using a repeated-dose approach. The hPSC-derived hepatocytes became more sensitive to the toxic compounds after extended exposures and, in addition to conventional cytotoxicity, evidence of phospholipidosis and steatosis was also observed in the cells. This is, to the best of our knowledge, the first report of a long-term toxicity study using hPSC-derived hepatocytes, and the observations support further development and validation of hPSC-based toxicity models for evaluating novel drugs, chemicals, and cosmetics.

  • 18.
    Holmgren, Gustav
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca Gothenburg, CVMD GMed, GMD, Mölndal, Sweden.
    MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity2016Inngår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 34, s. 26-34Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anthracyclines, such as doxorubicin, are well-established, highly efficient anti-neoplastic drugs used for treatment of a variety of cancers, including solid tumors, leukemia, lymphomas, and breast cancer. The successful use of doxorubicin has, however, been hampered by severe cardiotoxic side-effects. In order to prevent or reverse negative side-effects of doxorubicin, it is important to find early biomarkers of heart injury and drug-induced cardiotoxicity. The high stability under extreme conditions, presence in various body fluids, and tissue-specificity, makes microRNAs very suitable as clinical biomarkers. The present study aimed towards evaluating the early and late effects of doxorubicin on the microRNA expression in cardiomyocytes derived from human pluripotent stem cells. We report on several microRNAs, including miR-34a, miR-34b, miR-187, miR-199a, miR-199b, miR-146a, miR-15b, miR-130a, miR-214, and miR-424, that are differentially expressed upon, and after, treatment with doxorubicin. Investigation of the biological relevance of the identified microRNAs revealed connections to cardiomyocyte function and cardiotoxicity, thus supporting the findings of these microRNAs as potential biomarkers for drug-induced cardiotoxicity.

  • 19.
    Holmgren, Gustav
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Bogestål, Yalda
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. SP Chemistry Materials and Surfaces, Gothenburg, Sweden.
    Améen, Caroline
    Takara Bio Europe AB (former Cellectis AB), Gothenburg, Sweden.
    Åkesson, Karolina
    Takara Bio Europe AB (former Cellectis AB), Gothenburg, Sweden.
    Holmgren, Sandra
    Takara Bio Europe AB (former Cellectis AB), Gothenburg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Takara Bio Europe AB (former Cellectis AB), Gothenburg, Sweden / GMed CVMD, AstraZeneca, Mölndal.
    Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells2015Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 328, s. 102-111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days' exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular mechanisms behind the late onset apoptosis associated with doxorubicin-induced cardiomyopathy.

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  • 20.
    Holmgren, Gustav
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Asplund, Annika
    R&D, Hepatocyte Product Development, Takara Bio Europe AB, Gothenburg, Sweden.
    Toet, Karin
    Department of Metabolic Health Research, TNO, Leiden, The Netherlands.
    Andersson, Christian X.
    R&D, Hepatocyte Product Development, Takara Bio Europe AB, Gothenburg, Sweden.
    Hammarstedt, Ann
    The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Hanemaaijer, Roeland
    Department of Metabolic Health Research, TNO, Leiden, The Netherlands.
    Küppers-Munther, Barbara
    R&D, Hepatocyte Product Development, Takara Bio Europe AB, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases2020Inngår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, nr 2, artikkel-id E469Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is a strong anticipated future for human induced pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far, their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g., Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, low-density lipoproteins (LDL), and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker tumor necrosis factor α (TNFα) was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling non-alcoholic steatohepatitis (NASH). Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.

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  • 21.
    Johansson, Markus
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Tangruksa, Benyapa
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Data Mining Identifies CCN2 and THBS1 as Biomarker Candidates for Cardiac Hypertrophy2022Inngår i: Life, E-ISSN 2075-1729, Vol. 12, nr 5, artikkel-id 726Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiac hypertrophy is a condition that may contribute to the development of heart failure. In this study, we compare the gene-expression patterns of our in vitro stem-cell-based cardiac hypertrophy model with the gene expression of biopsies collected from hypertrophic human hearts. Twenty-five differentially expressed genes (DEGs) from both groups were identified and the expression of selected corresponding secreted proteins were validated using ELISA and Western blot. Several biomarkers, including CCN2, THBS1, NPPA, and NPPB, were identified, which showed significant overexpressions in the hypertrophic samples in both the cardiac biopsies and in the endothelin-1-treated cells, both at gene and protein levels. The protein-interaction network analysis revealed CCN2 as a central node among the 25 overlapping DEGs, suggesting that this gene might play an important role in the development of cardiac hypertrophy. GO-enrichment analysis of the 25 DEGs revealed many biological processes associated with cardiac function and the development of cardiac hypertrophy. In conclusion, we identified important similarities between ET-1-stimulated human-stem-cell-derived cardiomyocytes and human hypertrophic cardiac tissue. Novel putative cardiac hypertrophy biomarkers were identified and validated on the protein level, lending support for further investigations to assess their potential for future clinical applications. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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  • 22.
    Johansson, Markus
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals, R&D AstraZeneca, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden / Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Late-stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Cardiac hypertrophy in a dish: a human stem cell based model2020Inngår i: Biology open, ISSN 2046-6390, Vol. 9, nr 9, artikkel-id bio052381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiac hypertrophy is an important and independent risk factor for the development of heart failure. To better understand the mechanisms and regulatory pathways involved in cardiac hypertrophy, there is a need for improved in vitro models. In this study, we investigated how hypertrophic stimulation affected human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). The cells were stimulated with endothelin-1 (ET-1) for 8, 24, 48, 72, or 96 h. Parameters including cell size, ANP-, proBNP-, and lactate concentration were analyzed. Moreover, transcriptional profiling using RNA-sequencing was performed to identify differentially expressed genes following ET-1 stimulation. The results show that the CMs increase in size by approximately 13% when exposed to ET-1 in parallel to increases in ANP and proBNP protein and mRNA levels. Furthermore, the lactate concentration in the media was increased indicating that the CMs consume more glucose, a hallmark of cardiac hypertrophy. Using RNA-seq, a hypertrophic gene expression pattern was also observed in the stimulated CMs. Taken together, these results show that hiPSC-derived CMs stimulated with ET-1 display a hypertrophic response. The results from this study also provide new molecular insights about the underlying mechanisms of cardiac hypertrophy and may help accelerate the development of new drugs against this condition.

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  • 23.
    Johansson, Markus
    et al.
    Högskolan i Skövde, Forskningsmiljön Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap. Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Forskningsmiljön Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap.
    Andersson, Christian X.
    BioPharmaceuticals R&D Cell Therapy, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D AstraZeneca, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Forskningsmiljön Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap.
    Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy2022Inngår i: Life, E-ISSN 2075-1729, Vol. 12, nr 2, artikkel-id 293Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiac hypertrophy is an important and independent risk factor for the development of cardiac myopathy that may lead to heart failure. The mechanisms underlying the development of cardiac hypertrophy are yet not well understood. To increase the knowledge about mechanisms and regulatory pathways involved in the progression of cardiac hypertrophy, we have developed a human induced pluripotent stem cell (hiPSC)-based in vitro model of cardiac hypertrophy and performed extensive characterization using a multi-omics approach. In a series of experiments, hiPSC-derived cardiomyocytes were stimulated with Endothelin-1 for 8, 24, 48, and 72 h, and their transcriptome and secreted proteome were analyzed. The transcriptomic data show many enriched canonical pathways related to cardiac hypertrophy already at the earliest time point, e.g., cardiac hypertrophy signaling. An integrated transcriptome–secretome analysis enabled the identification of multimodal biomarkers that may prove highly relevant for monitoring early cardiac hypertrophy progression. Taken together, the results from this study demonstrate that our in vitro model displays a hypertrophic response on both transcriptomic- and secreted-proteomic levels. The results also shed novel insights into the underlying mechanisms of cardiac hypertrophy, and novel putative early cardiac hypertrophy biomarkers have been identified that warrant further investigation to assess their potential clinical relevance.

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  • 24.
    Jonsson, Malin K. B.
    et al.
    Genome Institute of Singapore, Genome, Singapore.
    van Veen, Toon A. B.
    Department of Medical Physiology, Division of Heart & Lungs, UMC Utrecht, Utrecht, Netherlands.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Becker, Bruno
    Department of Psychiatry and Neurochemistry, Sahlgrenska University Hospital, Mölndal, Sweden.
    Towards Creating the Perfect In Vitro Cell Model2016Inngår i: Stem Cells International, ISSN 1687-9678, Vol. 2016, artikkel-id 3459730Artikkel i tidsskrift (Fagfellevurdert)
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  • 25.
    Küppers-Munther, Barbara
    et al.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, A.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Abadie, A.
    Takara Bio Europe SAS, Paris, France.
    Novel human iPSC-derived hepatocytes with advanced functionality and long-term 2D cultures of human primary hepatocytes for metabolic disease studies2018Inngår i: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, nr 12, s. A146-A146, artikkel-id P406Artikkel i tidsskrift (Fagfellevurdert)
  • 26.
    Larsson, Susanna
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Holmgren, Sandra
    VERIGRAFT, Gothenburg, Sweden.
    Jenndahl, Lachmi
    VERIGRAFT, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Strehl, Raimund
    VERIGRAFT, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ghosheh, Nidal
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Proteome of Personalized Tissue-Engineered Veins2024Inngår i: ACS Omega, E-ISSN 2470-1343, Vol. 9, nr 13, s. 14805-14817Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vascular diseases are the largest cause of death globally and impose a major global burden on healthcare. The gold standard for treating vascular diseases is the transplantation of autologous veins, if applicable. Alternative treatments still suffer from shortcomings, including low patency, lack of growth potential, the need for repeated intervention, and a substantial risk of developing infections. The use of a vascular ECM scaffold reconditioned with the patient's own cells has shown successful results in preclinical and clinical studies. In this study, we have compared the proteomes of personalized tissue-engineered veins of humans and pigs. By applying tandem mass tag (TMT) labeling LC/MS-MS, we have investigated the proteome of decellularized (DC) veins from humans and pigs and reconditioned (RC) DC veins produced through perfusion with the patient's whole blood in STEEN solution, applying the same technology as used in the preclinical studies. The results revealed high similarity between the proteomes of human and pig DC and RC veins, including the ECM texture after decellularization and reconditioning. In addition, functional enrichment analysis showed similarities in signaling pathways and biological processes involved in the immune system response. Furthermore, the classification of proteins involved in immune response activity that were detected in human and pig RC veins revealed proteins that evoke immunogenic responses, which may lead to graft rejection, thrombosis, and inflammation. However, the results from this study imply the initiation of wound healing rather than an immunogenic response, as both systems share the same processes, and no immunogenic response was reported in the preclinical and clinical studies. Finally, our study assessed the application of STEEN solution in tissue engineering and identified proteins that may be useful for the prediction of successful transplantations. 

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  • 27.
    Lundin, Anders
    et al.
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Delsing, Louise
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Clausen, Maryam
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ricchiuto, Piero
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sanchez, José
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sabirsh, Alan
    Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ding, Mei
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK / UK Dementia Research Institute at UCL, London, UK.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Herland, Anna
    Department of Micro and Nanosystems KTH Royal Institute of Technology, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models2018Inngår i: Stem Cell Reports, ISSN 2213-6711, Vol. 10, nr 3, s. 1030-1045Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology.

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  • 28.
    Magnusson, Lisa U.
    et al.
    Sahlgrenska Academy, University of Gothenburg.
    Lundqvist, Annika
    Sahlgrenska Academy, University of Gothenburg.
    Asp, Julia
    Sahlgrenska Academy, University of Gothenburg.
    Synnergren, Jane
    Högskolan i Skövde, Forskningscentrum för Systembiologi. Högskolan i Skövde, Institutionen för vård och natur.
    Thalén Johansson, Cecilia
    Sahlgrenska Academy, University of Gothenburg.
    Palmqvist, Lars
    Sahlgrenska Academy, University of Gothenburg.
    Jeppsson, Anders
    Sahlgrenska University Hospital.
    Mattsson Hultén, Lillemor
    Sahlgrenska Academy, University of Gothenburg.
    High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue2012Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 424, nr 2, s. 327-330Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A common feature of the ischemic heart and atherosclerotic plaques is the presence of hypoxia (insufficient levels of oxygen in the tissue). Hypoxia has pronounced effects on almost every aspect of cell physiology, and the nuclear transcription factor hypoxia inducible factor-1α (HIF-1α) regulates adaptive responses to low concentrations of oxygen in mammalian cells. In our recent work, we observed that hypoxia increases the proinflammatory enzyme arachidonate 15-lipoxygenase (ALOX15B) in human carotid plaques. ALOX15 has recently been shown to be present in the human myocardium, but the effect of ischemia on its expression has not been investigated. Here we test the hypothesis that ischemia of the heart leads to increased expression of ALOX15, and found an almost 2-fold increase in HIF-1α mRNA expression and a 17-fold upregulation of ALOX15 mRNA expression in the ischemic heart biopsies from patients undergoing coronary bypass surgery compared with non ischemic heart tissue. To investigate the effect of low oxygen concentration on ALOX15 we incubated human vascular muscle cells in hypoxia and showed that expression of ALOX15 increased 22-fold compared with cells incubated in normoxic conditions. We also observed increased mRNA levels of proinflammatory markers in ischemic heart tissue compared with non-ischemic controls. In summary, we demonstrate increased ALOX15 in human ischemic heart biopsies. Furthermore we demonstrate that hypoxia increases ALOX15 in human muscle cells. Our results yield important insights into the underlying association between hypoxia and inflammation in the human ischemic heart disease.

  • 29.
    Marzec-Schmidt, Katarzyna
    et al.
    Department of Soil and Environment, Swedish University of Agricultural Sciences (SLU), Skara, Sweden.
    Ghosheh, Nidal
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Takara Bio Europe, Gothenburg, Sweden.
    Stahlschmidt, Sören Richard
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Küppers-Munther, Barbara
    Takara Bio Europe, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Artificial intelligence supports automated characterization of differentiated human pluripotent stem cells2023Inngår i: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 41, nr 9, s. 850-861, artikkel-id sxad049Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Revolutionary advances in AI and deep learning in recent years have resulted in an upsurge of papers exploring applications within the biomedical field. Within stem cell research, promising results have been reported from analyses of microscopy images to e.g., distinguish between pluripotent stem cells and differentiated cell types derived from stem cells. In this work, we investigated the possibility of using a deep learning model to predict the differentiation stage of pluripotent stem cells undergoing differentiation towards hepatocytes, based on morphological features of cell cultures. We were able to achieve close to perfect classification of images from early and late time points during differentiation, and this aligned very well with the experimental validation of cell identity and function. Our results suggest that deep learning models can distinguish between different cell morphologies, and provide alternative means of semi-automated functional characterization of stem cell cultures.

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  • 30.
    Nawaz, Muhammad
    et al.
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Tangruksa, Benyapa
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    González-King Garibotti, Hernán
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Jing, Yujia
    Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Maugeri, Marco
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Safety Innovations, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca, Gothenburg, Mölndal, Sweden.
    Kohl, Franziska
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden ; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Solna, Sweden.
    Hultin, Leif
    BioPharmaceuticals R&D, Clinical Pharmacology and Safety Science, Imaging and Data Analytics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Reyahi, Azadeh
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Camponeschi, Alessandro
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Kull, Bengt
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Christoffersson, Jonas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Grimsholm, Ola
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Austria.
    Jennbacken, Karin
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Sundqvist, Martina
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Wiseman, John
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Bidar, Abdel Wahad
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Lindfors, Lennart
    Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Valadi, Hadi
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Lipid Nanoparticles Deliver the Therapeutic VEGFA mRNA In Vitro and In Vivo and Transform Extracellular Vesicles for Their Functional Extensions2023Inngår i: Advanced Science, E-ISSN 2198-3844, Vol. 10, nr 12, artikkel-id 2206187Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID-19 mRNA vaccines. The delivery of angiogenic molecules, such as therapeutic VEGF-A mRNA, to ischemic tissues for producing new blood vessels is an emerging strategy for the treatment of cardiovascular diseases. Here, the authors deliver VEGF-A mRNA via LNPs and study stoichiometric quantification of their uptake kinetics and how the transport of exogenous LNP-mRNAs between cells is functionally extended by cells’ own vehicles called extracellular vesicles (EVs). The results show that cellular uptake of LNPs and their mRNA molecules occurs quickly, and that the translation of exogenously delivered mRNA begins immediately. Following the VEGF-A mRNA delivery to cells via LNPs, a fraction of internalized VEGF-A mRNA is secreted via EVs. The overexpressed VEGF-A mRNA is detected in EVs secreted from three different cell types. Additionally, RNA-Seq analysis reveals that as cells’ response to LNP-VEGF-A mRNA treatment, several overexpressed proangiogenic transcripts are packaged into EVs. EVs are further deployed to deliver VEGF-A mRNA in vitro and in vivo. Upon equal amount of VEGF-A mRNA delivery via three EV types or LNPs in vitro, EVs from cardiac progenitor cells are the most efficient in promoting angiogenesis per amount of VEGF-A protein produced. Intravenous administration of luciferase mRNA shows that EVs could distribute translatable mRNA to different organs with the highest amounts of luciferase detected in the liver. Direct injections of VEGF-A mRNA (via EVs or LNPs) into mice heart result in locally produced VEGF-A protein without spillover to liver and circulation. In addition, EVs from cardiac progenitor cells cause minimal production of inflammatory cytokines in cardiac tissue compared with all other treatment types. Collectively, the data demonstrate that LNPs transform EVs as functional extensions to distribute therapeutic mRNA between cells, where EVs deliver this mRNA differently than LNPs. 

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  • 31.
    Riveiro, Maria
    et al.
    Högskolan i Skövde, Institutionen för informationsteknologi. Högskolan i Skövde, Forskningscentrum för Informationsteknologi.
    Lebram, Mikael
    Högskolan i Skövde, Institutionen för informationsteknologi. Högskolan i Skövde, Forskningscentrum för Informationsteknologi.
    Andersson, Christian X.
    Takara Bio Europe, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Astra Zeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Interactive visualization of large-scale gene expression data2016Inngår i: Information Visualisation: Computer Graphics, Imaging and Visualisation / [ed] Ebad Banissi, Mark W. McK. Bannatyne, Fatma Bouali, Remo Burkhard, John Counsell, Urska Cvek, Martin J. Eppler, Georges Grinstein, Wei Dong Huang, Sebastian Kernbach, Chun-Cheng Lin, Feng Lin, Francis T. Marchese, Chi Man Pun, Muhammad Sarfraz, Marjan Trutschl, Anna Ursyn, Gilles Venturini, Theodor G. Wyeld, and Jian J. Zhang, IEEE Computer Society, 2016, s. 348-354Konferansepaper (Fagfellevurdert)
    Abstract [en]

    In this article, we present an interactive prototype that aids the interpretation of large-scale gene expression data, showing how visualization techniques can be applied to support knowledge extraction from large datasets. The developed prototype was evaluated on a dataset of human embryonic stem cell-derived cardiomyocytes. The visualization approach presented here supports the analyst in finding genes with high similarity or dissimilarity across different experimental groups. By using an external overview in combination with filter windows, and various color scales for showing the degree of similarity, our interactive visual prototype is able to intuitively guide the exploration processes over the large amount of gene expression data.

  • 32.
    Sandstedt, Mikael
    et al.
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Vukusic, Kristina
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Johansson, Markus
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Jonsson, Marianne
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Magnusson, Rasmus
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Hultén, Lillemor Mattsson
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dellgren, Göran
    Molecular and Clinical Medicine, Cardiothoracic Surgery, University of Gothenburg, Sweden.
    Jeppsson, Anders
    Molecular and Clinical Medicine, Cardiothoracic Surgery, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lindahl, Anders
    Sahlgrenska University Hospital, Göteborg, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Sandstedt, Joakim
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Regional transcriptomic profiling reveals immune system enrichment in nonfailing atria as well as all chambers of the failing human heart2023Inngår i: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 325, nr 6, s. H1430-H1445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The different chambers of the human heart demonstrate regional physiological traits and may be differentially affected during pathologic remodeling, resulting in heart failure. Few previous studies have, however, characterized the different chambers at a transcriptomic level. We therefore conducted whole-tissue RNA sequencing and gene set enrichment analysis of biopsies collected from the four chambers of adult failing (n = 8) and nonfailing (n = 11) human hearts. Atria and ventricles demonstrated distinct transcriptional patterns. Compared to nonfailing ventricles, the transcriptional pattern of nonfailing atria was enriched for a large number of gene sets associated with cardiogenesis, the immune system and bone morphogenetic protein (BMP), transforming growth factor beta (TGF beta), MAPK/JNK and Wnt signaling. Differences between failing and nonfailing hearts were also determined. The transcriptional pattern of failing atria was distinct compared to that of nonfailing atria and enriched for gene sets associated with the innate and adaptive immune system, TGF beta/SMAD signaling, and changes in endothelial, smooth muscle cell and cardiomyocyte physiology. Failing ventricles were also enriched for gene sets associated with the immune system. Based on the transcriptomic patterns, upstream regulators associated with heart failure were identified. These included many immune response factors predicted to be similarly activated for all chambers of failing hearts. In summary, the heart chambers demonstrate distinct transcriptional patterns that differ between failing and nonfailing hearts. Immune system signaling may be a hallmark of all four heart chambers in failing hearts, and could constitute a novel therapeutic target.

  • 33.
    Sandstedt, Mikael
    et al.
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vukusic, Kristina
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Jonsson, Marianne
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Mattsson Hultén, Lillemor
    Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Universityof Gothenburg, Sweden.
    Dellgren, Göran
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Universityof Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Region Västra Götaland, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Universityof Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Region Västra Götaland, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Sandstedt, Joakim
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Human intracardiac SSEA4+CD34 cells show features of cycling, immature cardiomyocytes and are distinct from Side Population and C-kit+CD45- cells2022Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 17, nr 6, artikkel-id e0269985Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiomyocyte proliferation has emerged as the main source of new cardiomyocytes in the adult. Progenitor cell populations may on the other hand contribute to the renewal of other cell types, including endothelial and smooth muscle cells. The phenotypes of immature cell populations in the adult human heart have not been extensively explored. We therefore investigated whether SSEA4+CD34- cells might constitute immature cycling cardiomyocytes in the adult failing and non-failing human heart. The phenotypes of Side Population (SP) and C-kit+CD45- progenitor cells were also analyzed. Biopsies from the four heart chambers were obtained from patients with end-stage heart failure as well as organ donors without chronic heart failure. Freshly dissociated cells underwent flow cytometric analysis and sorting. SSEA4+CD34- cells expressed high levels of cardiomyocyte, stem cell and proliferation markers. This pattern resembles that of cycling, immature, cardiomyocytes, which may be important in endogenous cardiac regeneration. SSEA4+CD34- cells isolated from failing hearts tended to express lower levels of cardiomyocyte markers as well as higher levels of stem cell markers. C-kit+CD45- and SP CD45- cells expressed high levels of endothelial and stem cell markers-corresponding to endothelial progenitor cells involved in endothelial renewal.

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  • 34.
    Sartipy, P.
    et al.
    Cellartis AB, Arvid Wallgrens Backe 20, SE-413 46 Göteborg, Sweden.
    Olsson, Björn
    Högskolan i Skövde, Forskningscentrum för Systembiologi. Högskolan i Skövde, Institutionen för vård och natur.
    Hyllner, J.
    Cellartis AB, Arvid Wallgrens Backe 20, SE-413 46 Göteborg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Forskningscentrum för Systembiologi. Högskolan i Skövde, Institutionen för vård och natur.
    Regulation of 'stemness' and stem cell differentiation by microRNAs2009Inngår i: IDrugs. The Investigational Drugs Journal, ISSN 1369-7056, E-ISSN 2040-3410, Vol. 12, nr 8, s. 492-496Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Pluripotency and cellular differentiation are intricate biological processes that are coordinately regulated by a complex set of factors and epigenetic regulators. Human pluripotent stem cell lines can be generated from surplus fertilized eggs or, as demonstrated more recently, from the reprogramming of somatic cells. Standardized culture conditions for the long-term maintenance and propagation of undifferentiated human pluripotent stem cells have also been developed. An objective of current research is to increase the understanding of the molecular mechanisms that regulate stem cell differentiation. The differentiation of human pluripotent stem cells may enable the generation of large quantities of specialized cells that can be used as in vitro tools for drug development, as well as for future applications in regenerative medicine. However, most of the currently used differentiation protocols yield inefficient stem cell quantities and low purity of the final cell preparations. The discovery of microRNAs (miRNAs) and their role as important transcriptional regulators may provide a new means of manipulating stem cell fate. This article provides an overview of some recent advancements made in the fields of both stem cell biology and miRNA.

  • 35.
    Sartipy, Peter
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Holmgren, Gustav
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Andersson, Christian
    Takara Bio, Gothenburg, Sweden.
    Lindahl, Anders
    University of Gothenburg, Sweden.
    Visual integration of multiple omics data from human pluripotent stem cell-derived cardiomyocytes2017Konferansepaper (Fagfellevurdert)
  • 36.
    Sivertsson, Louise
    et al.
    Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Jensen, Janne
    Cellectis Stem Cells, Cellartis AB, Göteborg, Sweden.
    Björquist, Petter
    Cellectis Stem Cells, Cellartis AB, Göteborg, Sweden.
    Ingelman-Sundberg, Magnus
    Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Hepatic differentiation and maturation of human embryonic stem cells cultured in a perfused three-dimensional bioreactor2013Inngår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 22, nr 4, s. 581-594Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drug-induced liver injury is a serious and frequently occurring adverse drug reaction in the clinics and is hard to predict during preclinical studies. Today, primary hepatocytes are the most frequently used cell model for drug discovery and prediction of toxicity. However, their use is marred by high donor variability regarding drug metabolism and toxicity, and instable expression levels of liver-specific genes such as cytochromes P450. An in vitro model system based on human embryonic stem cells (hESC), with their unique properties of pluripotency and self-renewal, has potential to provide a stable and unlimited supply of human hepatocytes. Much effort has been made to direct hESC toward the hepatic lineage, mostly using 2-dimensional (2D) cultures. Although the results are encouraging, these cells lack important functionality. Here, we investigate if hepatic differentiation of hESC can be improved by using a 3-dimensional (3D) bioreactor system. Human ESCs were differentiated toward the hepatic lineage using the same cells in either the 3D or 2D system. A global transcriptional analysis identified important differences between the 2 differentiation regimes, and we identified 10 pathways, highly related to liver functions, which were significantly upregulated in cells differentiated in the bioreactor compared to 2D control cultures. The enhanced hepatic differentiation observed in the bioreactor system was also supported by immunocytochemistry. Taken together, our results suggest that hepatic differentiation of hESC is improved when using this 3D bioreactor technology as compared to 2D culture systems.

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  • 37.
    Sjölin, Jacob
    et al.
    Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jonsson, Marianne
    Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Orback, Charlotta
    Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Pathology, and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vukusic, Kristina
    Department of Laboratory Medicine, Institute of Biomedicine, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Expression of Stem Cell Niche-Related Biomarkers at the Base of the Human Tricuspid Valve2023Inngår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 32, nr 5-6, s. 140-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stem cell niches have been thoroughly investigated in tissue with high regenerative capacity but not in tissues where cell turnover is slow, such as the human heart. The left AtrioVentricular junction (AVj), the base of the mitral valve, has previously been proposed as a niche region for cardiac progenitors in the adult human heart. In the present study, we explore the right side of the human heart, the base of the tricuspid valve, to investigate the potential of this region as a progenitor niche. Paired biopsies from explanted human hearts were collected from multi-organ donors (N = 12). The lateral side of the AVj, right atria (RA), and right ventricle (RV) were compared for the expression of stem cell niche-related biomarkers using RNA sequencing. Gene expression data indicated upregulation of genes related to embryonic development and extracellular matrix (ECM) composition in the proposed niche region, that is, the AVj. In addition, immunohistochemistry showed high expression of the fetal cardiac markers MDR1, SSEA4, and WT1 within the same region. Nuclear expression of HIF1α was detected suggesting hypoxia. Rare cells were found with the co-staining of the proliferation marker PCNA and Ki67 with cardiomyocyte nuclei marker PCM1 and cardiac Troponin T (cTnT), indicating proliferation of small cardiomyocytes. WT1+/cTnT+ and SSEA4+/cTnT+ cells were also found, suggesting cardiomyocyte-specific progenitors. The expression of the stem cell markers gradually decreased with distance from the tricuspid valve. No expression of these markers was observed in the RV tissue. In summary, the base of the tricuspid valve is an ECM-rich region containing cells with expression of several stem cell niche-associated markers. Co-expression of stem cell markers with cTnT indicates cardiomyocyte-specific progenitors. We previously reported similar data from the base of the mitral valve and thus propose that human adult cardiomyocyte progenitors reside around both atrioventricular valves.

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  • 38.
    Skillbäck, Tobias
    et al.
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Delsing, Louise
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Mattsson, Niklas
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden / Department of Neurology, Skåne University Hospital, Lund, Sweden.
    Janelidze, Shorena
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Nägga, Katarina
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Kilander, Lena
    Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Wimo, Anders
    Centre for Research and Development, Uppsala University/County Council of Gävleborg, Gävle, Sweden / Division for Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
    Winblad, Bengt
    Division for Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden / Department Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden.
    Hansson, Oskar
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden / Department of Neurology, Skåne University Hospital, Lund, Sweden.
    Blennow, Kaj
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Eriksdotter, Maria
    Department Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden / Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
    Zetterberg, Henrik
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom / UK Dementia Research Institute at UCL, London, United Kingdom.
    CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients2017Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 59, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology.

  • 39.
    Stahlschmidt, Sören Richard
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Forskningsmiljön Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap.
    Synnergren, Jane
    Högskolan i Skövde, Forskningsmiljön Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap.
    Multimodal deep learning for biomedical data fusion: a review2022Inngår i: Briefings in Bioinformatics, ISSN 1467-5463, E-ISSN 1477-4054, Vol. 23, nr 2, artikkel-id bbab569Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Biomedical data are becoming increasingly multimodal and thereby capture the underlying complex relationships among biological processes. Deep learning (DL)-based data fusion strategies are a popular approach for modeling these nonlinear relationships. Therefore, we review the current state-of-the-art of such methods and propose a detailed taxonomy that facilitates more informed choices of fusion strategies for biomedical applications, as well as research on novel methods. By doing so, we find that deep fusion strategies often outperform unimodal and shallow approaches. Additionally, the proposed subcategories of fusion strategies show different advantages and drawbacks. The review of current methods has shown that, especially for intermediate fusion strategies, joint representation learning is the preferred approach as it effectively models the complex interactions of different levels of biological organization. Finally, we note that gradual fusion, based on prior biological knowledge or on search strategies, is a promising future research path. Similarly, utilizing transfer learning might overcome sample size limitations of multimodal data sets. As these data sets become increasingly available, multimodal DL approaches present the opportunity to train holistic models that can learn the complex regulatory dynamics behind health and disease.

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  • 40.
    Stahlschmidt, Sören Richard
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden.
    Predicting Cancer Stage from Circulating microRNA: A Comparative Analysis of Machine Learning Algorithms2023Inngår i: Bioinformatics and Biomedical Engineering: 10th International Work-Conference, IWBBIO 2023, Meloneras, Gran Canaria, Spain, July 12–14, 2023, Proceedings, Part I / [ed] Ignacio Rojas; Olga Valenzuela; Fernando Rojas Ruiz; Luis Javier Herrera; Francisco Ortuño, Cham: Springer, 2023, s. 103-115Konferansepaper (Fagfellevurdert)
    Abstract [en]

    In recent years, serum-based tests for early detection and detection of tissue of origin are being developed. Circulating microRNA has been shown to be a potential source of diagnostic information that can be collected non-invasively. In this study, we investigate circulating microRNAs as predictors of cancer stage. Specifically, we predict whether a sample stems from a patient with early stage (0-II) or late stage cancer (III-IV). We trained five machine learning algorithms on a data set of cancers from twelve different primary sites. The results showed that cancer stage can be predicted from circulating microRNA with a sensitivity of 71.73%, specificity of 79.97%, as well as positive and negative predictive value of 54.81% and 89.29%, respectively. Furthermore, we compared the best pan-cancer model with models specialized on individual cancers and found no statistically significant difference. Finally, in the best performing pan-cancer model 185 microRNAs were significant. Comparing the five most relevant circulating microRNAs in the best performing model with the current literature showed some known associations to various cancers. In conclusion, the study showed the potential of circulating microRNA and machine learning algorithms to predict cancer stage and thus suggests that further research into its potential as a non-invasive clinical test is warranted. 

  • 41.
    Starokozhko, Viktoriia
    et al.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
    Vatakuti, Suresh
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
    Schievink, Bauke H.
    Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
    Merema, Marjolijn T.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
    Asplund, Annika
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Aspegren, Anders
    Takara Bio Europe AB, Gothenburg, Sweden.
    Groothuis, Geny M. M.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
    Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days2017Inngår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, nr 5, s. 2079-2092Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and function of hPCLS to 5 days of incubation. hPCLS were incubated in two media developed for long-term culture of hepatocytes, RegeneMed(®), and Cellartis(®), and in the standard medium WME. Maintenance of phase I and II metabolism was studied both on gene expression as well as functional level using a mixture of CYP isoform-specific substrates. Albumin synthesis, morphological integrity, and glycogen storage was assessed, and gene expression was studied by transcriptomic analysis using microarrays with a focus on genes involved in drug metabolism, transport and toxicity. The data show that hPCLS retain their viability and functionality during 5 days of incubation in Cellartis(®) medium. Albumin synthesis as well as the activity and gene expression of phase I and II metabolic enzymes did not decline during 120-h incubation in Cellartis(®) medium, with CYP2C9 activity as the only exception. Glycogen storage and morphological integrity were maintained. Moreover, gene expression changes in hPCLS during incubation were limited and mostly related to cytoskeleton remodeling, fibrosis, and moderate oxidative stress. The expression of genes involved in drug transport, which is an important factor in determining the intracellular xenobiotic exposure, was also unchanged. Therefore, we conclude that hPCLS cultured in Cellartis(®) medium are a valuable human ex vivo model for toxicological and pharmacological studies that require prolonged xenobiotic exposure.

    Fulltekst (pdf)
    fulltext
  • 42.
    Stenberg, Johan
    et al.
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    de Windt, Tommy S.
    Department of Orthopaedics, University Medical Center Utrecht, Utrecht, the Netherlands.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Hynsjö, Lars
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    van der Lee, Josefine
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Saris, Daniel B. F.
    Department of Orthopaedics, University Medical Center Utrecht, Utrecht, the Netherlands / MIRA Institute for Biotechnology and Technical Medicine, University of Twente, Enschede, the Netherlands.
    Brittberg, Mats
    Department of Orthopaedics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Peterson, Lars
    Department of Orthopaedics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Clinical Outcome 3 Years After Autologous Chondrocyte Implantation Does Not Correlate With the Expression of a Predefined Gene Marker Set in Chondrocytes Prior to Implantation but Is Associated With Critical Signaling Pathways2014Inngår i: The Orthopaedic Journal of Sports Medicine, ISSN 2325-9671, Vol. 2, nr 9, s. 1-14, artikkel-id 2325967114550781Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: There is a need for tools to predict the chondrogenic potency of autologous cells for cartilage repair.

    PURPOSE: To evaluate previously proposed chondrogenic biomarkers and to identify new biomarkers in the chondrocyte transcriptome capable of predicting clinical success or failure after autologous chondrocyte implantation.

    STUDY DESIGN: Controlled laboratory study and case-control study; Level of evidence, 3.

    METHODS: Five patients with clinical improvement after autologous chondrocyte implantation and 5 patients with graft failures 3 years after implantation were included. Surplus chondrocytes from the transplantation were frozen for each patient. Each chondrocyte sample was subsequently thawed at the same time point and cultured for 1 cell doubling, prior to RNA purification and global microarray analysis. The expression profiles of a set of predefined marker genes (ie, collagen type II α1 [COL2A1], bone morphogenic protein 2 [BMP2], fibroblast growth factor receptor 3 [FGFR3], aggrecan [ACAN], CD44, and activin receptor-like kinase receptor 1 [ACVRL1]) were also evaluated.

    RESULTS: No significant difference in expression of the predefined marker set was observed between the success and failure groups. Thirty-nine genes were found to be induced, and 38 genes were found to be repressed between the 2 groups prior to autologous chondrocyte implantation, which have implications for cell-regulating pathways (eg, apoptosis, interleukin signaling, and β-catenin regulation).

    CONCLUSION: No expressional differences that predict clinical outcome could be found in the present study, which may have implications for quality control assessments of autologous chondrocyte implantation. The subtle difference in gene expression regulation found between the 2 groups may strengthen the basis for further research, aiming at reliable biomarkers and quality control for tissue engineering in cartilage repair.

    CLINICAL RELEVANCE: The present study shows the possible limitations of using gene expression before transplantation to predict the chondrogenic and thus clinical potency of the cells. This result is especially important as the chondrogenic potential of the chondrocytes is currently part of quality control measures according to European and American legislations regarding advanced therapies.

    Fulltekst (pdf)
    fulltext
  • 43.
    Svala, Emilia
    et al.
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden / Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Thorfve, Anna I.
    BIOMATCELL, VINN Excellence Center of Biomaterials and Cell Therapy, Department of Biomaterials, Institute of Clinical Sciences, Sweden.
    Ley, Cecilia
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Henriksson, Helena K. Barreto
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Sweden / Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Synnergren, Jane M.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. University of Gothenburg, Sweden.
    Lindahl, Anders H.
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Sweden.
    Ekman, Stina
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Skiöldebrand, Eva S. R.
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden / Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Effects of interleukin-6 and interleukin-1β on expression of growth differentiation factor-5 and Wnt signaling pathway genes in equine chondrocytes2014Inngår i: American Journal of Veterinary Research, ISSN 0002-9645, E-ISSN 1943-5681, Vol. 75, nr 2, s. 132-140Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To determine the effects of interleukin (IL)-6 and IL-1β stimulation on expression of growth differentiation factor (GDF)-5 and Wnt signaling pathway genes in equine chondrocytes.

    SAMPLE: Macroscopically normal articular cartilage samples from 6 horses and osteochondral fragments (OCFs) from 3 horses.

    PROCEDURES: Chondrocyte pellets were prepared and cultured without stimulation or following stimulation with IL-6 or IL-1β for 1, 2, 12, and 48 hours; expression of GDF-5 was determined with a quantitative real-time PCR assay. Expression of genes in various signaling pathways was determined with microarrays for pellets stimulated for 1 and 2 hours. Immunohistochemical analysis was used to detect GDF-5, glycogen synthase kinase 3β (GSK-3β), and β-catenin proteins in macroscopically normal cartilage samples and OCFs.

    RESULTS: Chondrocytes stimulated with IL-6 had significantly higher GDF-5 expression within 2 hours versus unstimulated chondrocytes. Microarray analysis of Wnt signaling pathway genes indicated expression of GSK-3β and coiled-coil domain containing 88C increased after 1 hour and expression of β-catenin decreased after 2 hours of IL-6 stimulation. Results of immunohistochemical detection of proteins were similar to microarray analysis results. Chondrocytes in macroscopically normal articular cartilage and OCFs had immunostaining for GDF-5.

    CONCLUSION AND CLINICAL RELEVANCE: Results indicated IL-6 stimulation decreased chondrocyte expression of the canonical Wnt signaling pathway transactivator β-catenin, induced expression of inhibitors of the Wnt pathway, and increased expression of GDF-5. This suggested IL-6 may inhibit the Wnt signaling pathway with subsequent upregulation of GDF-5 expression. Anabolic extracellular matrix metabolism in OCFs may be attributable to GDF-5 expression. This information could be useful for development of cartilage repair methods.

  • 44.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Explore transcription factor profiles in human pluripotent stem cells2014Inngår i: 6th International Conference on Bioinformatics and Computational Biology (BICoB 2014): Las Vegas, Nevada, USA, 24 – 26 March 2014 / [ed] F. Saeed, B. DasGupta, International Society for Computers and Their Applications , 2014, s. 197-202Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Human pluripotent stem cells (hPSCs) have unique properties of proliferation and self-renewal, and can be differentiated into various functional cell types. The differentiation processes are to a large extent controlled by transcription factors, which are key cellular components that control gene expression and determine how cells respond to the environment on various stimuli. Surprisingly little is known about the transcription factor activity in hPSCs, and more knowledge is needed about the transcriptional regulation during the differentiation processes. This information will be instrumental for development of efficient differentiation protocols to produce fully functional specialized cell types, for use in drug discovery and toxicity testing studies. This paper explores the expression of transcription factors in hPSCs, and gives an overview of the genomic organization of transcription factors, which likely are involved in the fate decision processes of hPSCs. In total 1,323 human transcription factors were selected from literature and further investigated for their genomic organization and their expression in hPSCs. Moreover, transcription factors that are highly expressed in undifferentiated hPSCs, compared to their differentiated progenies are identified and further investigated for protein-protein interaction activity using computational tools. The protein-protein interaction networks presented here will provide valuable information about the regulatory mechanisms, and reveal important proteins involved in the maintenance of the pluripotent state of stem cells.

  • 45.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Identification of miRNAs in Control of Aberrant Gene Transcription in Human Pluripotent Stem Cell Derived Hepatocytes2013Inngår i: Computer Applications in Industry and Engineering (CAINE-2013), 26th International Conference September 25-27, 2013, Los Angeles, California, USA / [ed] Sultan Aljahdali, International Society for Computers and Their Applications , 2013, s. 11-16Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Human pluripotent stem cells (hPSCs) have unique properties of proliferation and self-renewal, and can be differentiated into various functional cell types e.g. hepatocytes. However, despite large effort in development of efficient differentiation protocols, hPSC-derived hepatocytes still lack some important functionality that prevents their use in drug discovery and toxicity testing studies. Novel approaches are therefore needed to improve the differentiation protocols, and produce more functional hepatocytes, which better mimic their in vivo counterparts. MicroRNAs (miRNAs) are small molecules, which play key roles in regulation of cellular development and may therefore be powerful tools to direct the differentiation. This paper identifies comprehensive miRNA regulatory networks, which may control the impaired hepatic functionality observed in hPSC-derived hepatocytes. An efficient method to derive miRNA-mRNA regulatory network is presented. The identified miRNAs are likely involved in the regulation of the hampered functionality observed in the hPSC-derived hepatocytes. In total 20 hepatocyte-related genes with known miss-regulation in hPSC-derived hepatocytes were identified from literature [1-5]. These genes are responsible for various types of functionality in the hepatocytes. This list of genes was investigated and scanned for putative miRNA target sites. For each of the predicted miRNAs, a target prediction score was calculated and miRNA regulatory networks were generated consisting of miRNAs with a high prediction score or with multiple targets among the investigated genes. Results from this study propose miRNA networks, which likely are highly involved in the hampered functionality observed in hPSC-derived hepatocytes. The presented miRNA-mRNA networks will provide valuable information when selecting candidate miRNAs for future knockout- and overexpression studies.

  • 46.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    MicroRNA regulatory network involved in impaired functionality in cardiomyocytes derived from human embryonic stem cells2012Inngår i: 25th International Conference on Computer Applications in Industry and Engineering 2012 (CAINE-2012) Held with the 4th International Symposium on Sensor Network and Application (SNA-2012): New Orleans, Louisiana, USA 14-16 November 2012 / [ed] Gongzhu Hu, International Society for Computers and Their Applications , 2012, s. 133-138Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Human embryonic stem cells (hESCs) have unique properties of proliferation and self-renewal, and can be differentiated into various functional cell types e.g. cardiomyocytes. However, previous studies have shown that the expression of cardiac ion channels and genes involved in the Ca2+-handling machinery is immature in the stem cell derived cardiomyocytes, and novel approaches are therefore needed to improve the differentiation protocols and produce more functional cardiomyocytes. MicroRNAs (miRNAs) are small molecules, which play key roles in regulation of cellular development and may therefore be powerful tools to improve the differentiation.

    This paper presents a method to derive a miRNA-mRNA regulatory network, which likely are important for the regulation of the functionality that currently is lacking in the hESC-derived cardiomyocytes. In total 14 ion channels and 9 calcium handling genes that have important roles in cardiac tissue and which have shown to be significantly lower expressed in hESC-derived cardiomyocytes compared to their in vivo counterpart, were investigated and scanned for putative miRNA target sites. For each of the predicted miRNAs, a combined prediction score (CPS) was calculated and a miRNA regulatory network was generated consisting of miRNAs with a high CPS and with multiple targets among the investigated genes. Results from this study propose that the miRNA network presented here is highly involved in the hampered functionality seen in hESC-derived cardiomyocytes, and that it therefore will constitute an important tool to select candidate miRNAs for future knockout- and overexpression studies.

  • 47.
    Synnergren, Jane
    Högskolan i Skövde, Forskningscentrum för Systembiologi. Högskolan i Skövde, Institutionen för vård och natur.
    Transcriptional profiling of human embryonic stem cells and their functional derivatives2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Human    embryonic    stem    cells    (hESCs)    represent    populations    of    pluripotent, undifferentiated  cells  with  unlimited  replication  capacity,  and  with  the  ability  to differentiate into any functional cell type in the human body. Based on these properties, hESCs  and  their  derivatives  provide  unique  model  systems  for  basic  research  on embryonic development. Also, industrial in vitro applications of hESCs are now beginning to  find  their  way  into  the  fields  of  drug  discovery  and  toxicology.  Moreover,  hESC-derivatives are anticipated to be promising resources for future cell replacement therapies. However, in order to fully utilize the potential of hESCs it is necessary to increase our knowledge about the processes that govern the differentiation of these cells. At present, some  of  the  major  challenges  in  stem  cell  research  are  heterogeneous  cell  populations, insufficient  yield  of  the  differentiated  cell  types  and  immature  derivatives  with  limited functionality.  To  address  these  problems,  a  better  understanding  of  the  regulatory mechanisms  that  control  the  lineage  commitment  is  needed.  The  aim  of  this  thesis  has been to increase the knowledge of the global transcriptional programs which are activated when  cells  differentiate  along  specific  pathways,  and  to  identify  key  genes  that  show differential expression at specific stages of differentiation. The results indicate that hESCs express a unique set of housekeeping genes that are stably expressed in this specific cell type  and  in  their  derivatives,  which  highlights  the  importance  of  proper  validation  of reference genes for usage in hESCs. Furthermore, an extensive characterization of hESCs and differentiated progenies of the cardiac and hepatic lineages has been conducted, and sets  of  differentially  expressed  genes  were  identified.  Two  different  protocols,  which mediate  definitive  and  primitive  endoderm  respectively,  were  studied,  and  important discrepancies  between  these  two  cell  types  were  identified.  Moreover,  the  global expression profile of hESC-derived cardiomyocyte clusters were thoroughly investigated and compared to that of foetal and adult heart. To further study regulatory mechanisms of  importance  during  stem  cell  differentiation,  the  global  expression  of  microRNAs (miRNAs) was also investigated. Putative target genes of differentially expressed miRNAs were  identified  using  computational  predictions,  and  their  mRNA  expression  was analysed. Notably, an interesting correlation between the miRNA and mRNA expression was observed, which supports the general notion that miRNAs bind to and degrade their target mRNAs, and thus act as fine-tuning regulators of gene expression. Taken together, the results described in this thesis provide important information for further studies on regulatory mechanisms that control the differentiation of hESCs into functional cell types such as cardiomyocytes and hepatocytes. 

  • 48.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för kommunikation och information.
    Understanding the differentiation of human embryonic stem cells2006Rapport (Annet vitenskapelig)
    Abstract [en]

    The proposed research project will apply an information fusion approach to various types of experimental data in order to increase our understanding of the differentiation of human embryonic stem (hES) cells into various specialized cell types. Gene expression profiles from hES cells in different stages of differentiation will be analysed to identify significantly over- and underexpressed genes. The purpose of the analysis is to find genes that might be important in the differentiation process and that are crucial for directing stem cells into specialized cell types. The project will focus on the endoderm development and one issue will be to increase our knowledge about two different types of endoderm development occurring in humans; primitive and definitive endoderm and their derivates. Another issue will be to compare gene expression profiles from cells that lack chromosome 13 with a sub-clone with normal karyotype (Heins et al., 2004). A comparison of gene expression profiles from in vitro derived specialized cells with gene expression profiles from adult cells from the same tissue type will also be conducted. The project will start, however, with an investigation and validation of “housekeeping genes”, which will be used for normalization and calibration of the gene expression levels in the subsequent analyses. The novelty of the project arises from the fact that most previous research in understanding the differentiation of ES cells has been done on animals (Yamada et al., 2002; Stainier, 2002; Asahina et al., 2004), while very little has been done on human ES cells. Since substantial differences both in morphology and in the gene expression pattern are well known between ES cells from these two organisms, it is important to characterize the genetic regulation of the processes responsible for these differences. This project will work with hES cells supplied by Cellartis, a company specialized in hES cell technologies.

    Fulltekst (pdf)
    FULLTEXT01
  • 49.
    Synnergren, Jane
    et al.
    Högskolan i Skövde, Institutionen för vård och natur.
    Adak, Sudeshna
    GE John F Welch Technol Ctr Export Promot Ind Pk, Bangalore, Karnataka, India.
    Englund, Mikael
    Celllartis AB, SE-43146 Gothenburg, Sweden.
    Giesler, Theresa
    GE Healthcare, Piscataway, NJ 08855 USA.
    Noaksson, Karin
    Celllartis AB, SE-43146 Gothenburg, Sweden.
    Lindahl, Anders
    Sahlgrens Univ Hosp, Dept Clin Chem Transfus Med, SE-41345 Gothenburg, Sweden.
    Nilsson, Patric
    Högskolan i Skövde, Institutionen för vård och natur.
    Nelson, Deirdre
    GE Global Res Ctr, Moscow 123098, Russia.
    Abbot, Stewart
    GE Global Res Ctr, Moscow 123098, Russia.
    Olsson, Björn
    Högskolan i Skövde, Institutionen för vård och natur.
    Sartipy, Peter
    Celllartis AB, SE-43146 Gothenburg, Sweden.
    Cardiomyogenic gene expression profiling of differentiating human embryonic stem cells2008Inngår i: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 134, nr 1-2, s. 162-170Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human embryonic stem cells (hESCs) can differentiate into a variety of specialized cell types. Thus, they provide a model system for embryonic development to investigate the molecular processes of cell differentiation and lineage commitment. The development of the cardiac lineage is easily detected in mixed cultures by the appearance of spontaneously contracting areas of cells. We performed gene expression profiling of undifferentiated and differentiating hESCs and monitored 468 genes expressed during cardiac development and/or in cardiac tissue. Their transcription during early differentiation of hESCs through embryoid bodies (EBs) was investigated and compared with spontaneously differentiating hESCs maintained on feeders in culture without passaging (high-density (HD) protocol). We observed a larger variation in the gene expression between cells from a single cell line that were differentiated using two different protocols than in cells from different cell lines that were cultured according to the same protocol. Notably, the EB protocol resulted in more reproducible transcription profiles than the HD protocol. The results presented here provide new information about gene regulation during early differentiation of hESCs with emphasis on the cardiomyogenic program. In addition, we also identified regulatory elements that could prove critical for the development of the cardiomyocyte lineage.

  • 50.
    Synnergren, Jane
    et al.
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital.
    Améen, Caroline
    Cellartis, Göteborg, Sweden.
    Jansson, Andreas
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Sartipy, Peter
    Cellartis, Göteborg, Sweden.
    Global transcriptional profiling reveals similarities and differences between human stem cell-derived cardiomyocyte clusters and heart tissue2012Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, nr 4, s. 245-258Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is now well documented that human embryonic stem cells (hESCs) can differentiate into functional cardiomyocytes. These cells constitute a promising source of material for use in drug development, toxicity testing, and regenerative medicine. To assess their utility as replacement or complement to existing models, extensive phenotypic characterization of the cells is required. In the present study, we used microarrays and analyzed the global transcription of hESC-derived cardiomyocyte clusters (CMCs) and determined similarities as well as differences compared with reference samples from fetal and adult heart tissue. In addition, we performed a focused analysis of the expression of cardiac ion channels and genes involved in the Ca2+-handling machinery, which in previous studies have been shown to be immature in stem cell-derived cardiomyocytes. Our results show that hESC-derived CMCs, on a global level, have a highly similar gene expression profile compared with human heart tissue, and their transcriptional phenotype was more similar to fetal than to adult heart. Despite the high similarity to heart tissue, a number of significantly differentially expressed genes were identified, providing some clues toward understanding the molecular difference between in vivo sourced tissue and stem cell derivatives generated in vitro. Interestingly, some of the cardiacrelated ion channels and Ca2+-handling genes showed differential expression between the CMCs and heart tissues. These genes may represent candidates for future genetic engineering to create hESC-derived CMCs that better mimic the phenotype of the cardiomyocytes present in the adult human heart.

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