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  • 1.
    Asplund, Annika
    et al.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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 cultures2017Conference paper (Refereed)
  • 2.
    Chaudhari, Aditi
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Krumlinde, Daniel
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden / Scientific Solutions, Stockholm, Sweden.
    Lundqvist, Annika
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Akyurek, Levent M
    Department of Medical Chemistry and Cell Biology, University of Gothenburg, Sweden.
    Bandaru, Sashidhar
    Department of Medical Chemistry and Cell Biology, University of Gothenburg, Sweden.
    Skalen, Kristina
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Stahlman, Marcus
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Boren, Jan
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Wettergren, Yvonne
    Department of Surgery, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Health and Education. Department of Medical and Clinical Genetics, University of Gothenburg, Sweden.
    Sopasakis, Victoria Rotter
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    p110 alpha Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110 alpha Kinase Activity2015In: Molecular and Cellular Biology, ISSN 0270-7306, Vol. 35, no 19, p. 3258-3273Article in journal (Refereed)
    Abstract [en]

    The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

  • 3.
    Delsing, Louise
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Barrier properties and transcriptome expression in human iPSC-derived models of the blood-brain barrier2018In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 36, no 12, p. 1816-1827Article in journal (Refereed)
    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.

  • 4.
    Delsing, Louise
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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 cells2017Conference paper (Refereed)
  • 5.
    Doktorova, Tatyana Y.
    et al.
    Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
    Yildirimman, Reha
    Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    Vinken, Mathieu
    Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
    Vilardell, Mireia
    Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    Vanhaecke, Tamara
    Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
    Gmuender, Hans
    Genedata AG, Basel, Switzerland.
    Bort, Roque
    Unit of Experimental Hepathology, University Hospital La Fe Valencia, Spain / Faculty of Medicine, Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain.
    Brolen, Gabriella
    Cellectis, Göteborg, Sweden.
    Holmgren, Gustav
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Cellectis, Göteborg, Sweden.
    Li, Ruoya
    Biopredic International, Rennes, France.
    Chesne, Christophe
    Biopredic International, Rennes, France.
    van Delft, Joost
    Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
    Kleinjans, Jos
    Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
    Castell, Jose
    Unit of Experimental Hepathology, University Hospital La Fe Valencia, Spain / Faculty of Medicine, Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain.
    Björquist, Petter
    Cellectis, Göteborg, Sweden.
    Herwig, Ralf
    Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    Rogiers, Vera
    Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
    Transcriptomic responses generated by hepatocarcinogens in a battery of liver-based in vitro models2013In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 34, no 6, p. 1393-1402Article in journal (Refereed)
    Abstract [en]

    As the conventional approach to assess the potential of a chemical to cause cancer in humans still includes the 2-year rodent carcinogenicity bioassay, development of alternative methodologies is needed. In the present study, the transcriptomics responses following exposure to genotoxic (GTX) and non-genotoxic (NGTX) hepatocarcinogens and non-carcinogens (NC) in five liver-based in vitro models, namely conventional and epigenetically stabilized cultures of primary rat hepatocytes, the human hepatoma-derived cell lines HepaRG and HepG2 and human embryonic stem cell-derived hepatocyte-like cells, are examined. For full characterization of the systems, several bioinformatics approaches are employed including gene-based, ConsensusPathDB-based and classification analysis. They provide convincingly similar outcomes, namely that upon exposure to carcinogens, the HepaRG generates a gene classifier (a gene classifier is defined as a selected set of characteristic gene signatures capable of distinguishing GTX, NGTX carcinogens and NC) able to discriminate the GTX carcinogens from the NGTX carcinogens and NC. The other in vitro models also yield cancer-relevant characteristic gene groups for the GTX exposure, but some genes are also deregulated by the NGTX carcinogens and NC. Irrespective of the tested in vitro model, the most uniformly expressed pathways following GTX exposure are the p53 and those that are subsequently induced. The NGTX carcinogens triggered no characteristic cancer-relevant gene profiles in all liver-based in vitro systems. In conclusion, liver-based in vitro models coupled with transcriptomics techniques, especially in the case when the HepaRG cell line is used, represent valuable tools for obtaining insight into the mechanism of action and identification of GTX carcinogens.

  • 6.
    Enroth, Helena
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Unilabs AB.
    Wefer, Hugo
    Clinical genomics, Science for Life Laboratories.
    Ljungström, Lars
    Dept. of Infectious Diseases, Skaraborg Hospital Skövde.
    Tilevik, Diana
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Bioscience.
    NGS pilot study of E. coli ESBL from patients with suspected sepsis2015Conference paper (Refereed)
  • 7.
    Fabre, Kristin M.
    et al.
    Microphysiological Systems Center of Excellence, Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca, Waltham, MA, United States.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden / Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Colclough, Nicola
    Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
    Crowther, Damian C.
    Neuroscience, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
    Ewart, Lorna
    Microphysiological Systems Center of Excellence, Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
    Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling: a case study for blood brain barrier research in a pharmaceutical setting2019In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 140, p. 129-135Article in journal (Refereed)
    Abstract [en]

    Microphysiological systems (MPS) may be able to provide the pharmaceutical industry models that can reflect human physiological responses to improve drug discovery and translational outcomes. With lack of efficacy being the primary cause for drug attrition, developing MPS disease models would help researchers identify novel targets, study mechanisms in more physiologically-relevant depth, screen for novel biomarkers and test/optimize various therapeutics (small molecules, nanoparticles and biologics). Furthermore, with advances in inducible pluripotent stem cell technology (iPSC), pharmaceutical companies can access cells from patients to help recreate specific disease phenotypes in MPS platforms. Combining iPSC and MPS technologies will contribute to our understanding of the complexities of neurodegenerative diseases and of the blood brain barrier (BBB) leading to development of enhanced therapeutics. © 2018

  • 8.
    Fors, John
    University of Skövde, School of Bioscience.
    Effectiveness of reduced-dose efavirenz in hiv therapy considering patient adherence2012Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Antiretroviral drugs have revolutionized HIV care and enabled better management of the infection thus allowing patients survive for many years. One proposed approach to increase access to such drugs in sub-Saharan Africa is to use of a reduced-dose alternative of the drug efavirenz, with 400 mg rather than regular 600 mg dose. This effectively would provide medication for 50 percent more persons with the same amount of active ingredient. However, antiretroviral drugs require high patient adherence to achieve intended therapeutic effect, and it is unclear if a reduced-dose therapy would have sufficient efficacy, and if it would lead to an increased risk of viral resistance.

    The time profile of drug plasma concentration and corresponding long-term viral load was estimated using integrated population PK/PD simulations, with model parameters based on selected research studies. The results suggest a reduced dose 400 mg, rather than 600 mg regular dose, efavirenz in HIV therapy would place strict demands on patients to maintain very high adherence levels, at least 80-90 percent, to maintain sufficient drug concentration in blood plasma, and to minimize risk of viral failure. However, it is relatively rare for HIV therapy programs in sub-Saharan Africa to consistently achieve such high adherence levels. In addition, if patients are co-administered rifampin, a drug widely used in TB care, this increases hepatic metabolism and plasma clearance rate, resulting in further reduced average drug plasma concentration. These findings suggest a reduced dose efavirenz treatment alternative may be most (only) relevant for patient categories expected to maintain high adherence; and in particular among persons who have been confirmed to have CYP2B6 genotype consistent with inherently lower drug metabolism. At usual adherence levels it is estimated a reduced dose alternative may increase the share of patients at risk of viral failure by 5 to 15 percent vs. regular dose of 600 mg.

  • 9.
    Ghosheh, Nidal
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Bioscience. 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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca Research and Development, Global Medicines Development Cardiovascular and Metabolic Diseases Global Medicines Development Unit, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue2017In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 49, no 8, p. 430-446Article in journal (Refereed)
    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.

  • 10.
    Holmgren, Gustav
    Sahlgrenska Academy at University of Gothenburg.
    In vitro toxicity testing using human pluripotent stem cell derivatives2016Doctoral thesis, comprehensive summary (Other academic)
  • 11.
    Holmgren, Gustav
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Ghosheh, Nidal
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca Research and Development, Global Medicines Development, Cardiovascular and Metabolic Diseases Global Medicines Development Unit, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Identification of stable reference genes in differentiating human pluripotent stem cells2015In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 47, no 6, p. 232-239Article in journal (Refereed)
    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.

  • 12.
    Holmgren, Gustav
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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 hepatocytes2014In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 42, no 9, p. 1401-1406Article in journal (Refereed)
    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.

  • 13.
    Holmgren, Gustav
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca Gothenburg, CVMD GMed, GMD, Mölndal, Sweden.
    MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 34, p. 26-34Article in journal (Refereed)
    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.

  • 14.
    Holmgren, Gustav
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Bogestål, Yalda
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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 cells2015In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 328, p. 102-111Article in journal (Refereed)
    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.

  • 15.
    Kia, Richard
    et al.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Kelly, Lorna
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Sison-Young, Rowena L. C.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Zhang, Fang
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Pridgeon, Chris S.
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Heslop, James A.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Metcalfe, Pete
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Kitteringham, Neil R.
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Baxter, Melissa
    Univ Manchester, Fac Life Sci, Manchester, England / Univ Cent Lancashire, Sch Med & Dent, Preston, England.
    Harrison, Sean
    Stem Cells Safer Med, London, England / Acad Hlth Sci Ctr, Fac Med & Human Sci, Ctr Endocrinol & Diabet,Inst Human Dev, Manchester, England.
    Hanley, Neil A.
    Stem Cells Safer Med, London, England / Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Med & Human Sci, Ctr Endocrinol & Diabet,Inst Human Dev, Manchester, England / Cent Manchester Univ Hosp NHS Fdn Trust, Endocrinol Dept, Manchester England.
    Burke, Zoe D.
    Stem Cells Safer Med, London, England / Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Storm,, Mike P.
    Stem Cells Safer Med, London, England / Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Welham, Melanie J.
    Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Tosh, David
    Stem Cells Safer Med, London, England / Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Küppers-Munther, Barbara
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Takara Bio Europe AB, Gothenburg, Sweden.
    Edsbagge, Josefina
    Takara Bio Europe AB, Gothenburg, Sweden.
    Lewis, Philip J. Starkey
    Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland.
    Bonner, Frank
    Stem Cells Safer Med, London, England.
    Harpur, Ernie
    Stem Cells Safer Med, London, England / Newcastle Univ, Inst Cellular Med, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
    Sidaway, James
    Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland / AstraZeneca R&D, Drug Safety & Metab, Cheshire, England.
    Bowes, Joanne
    Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland / AstraZeneca R&D, Drug Safety & Metab, Cheshire, England.
    Fenwick, Stephen W.
    Aintree Univ Hosp NHS Fdn Trust, North Western Hepatobiliary Unit, Liverpool, England.
    Malik, Hassan
    Aintree Univ Hosp NHS Fdn Trust, North Western Hepatobiliary Unit, Liverpool, England.
    Goldring, Chris E. P.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England / Stem Cells Safer Med, London England.
    Park, B. Kevin
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England / Stem Cells Safer Med, London, England.
    MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity2015In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 144, no 1, p. 173-185Article in journal (Refereed)
    Abstract [en]

    Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.

  • 16.
    Pradip, Arvind
    et al.
    Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Göteborg, Sweden / Novo Nordisk A/S, Stem Cell Development, Bagsværd, Denmark.
    Steel, Daniella
    Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Göteborg, Sweden / Horizon Discovery Ltd, Cambridge Research Park, Cambridge, UK.
    Jacobsson, Susanna
    Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Göteborg, Sweden.
    Holmgren, Gustav
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Göteborg, Sweden.
    Ingelman-Sundberg, Magnus
    Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Göteborg, Sweden / AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
    Björquist, Petter
    Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Göteborg, Sweden / Novo Nordisk A/S, Stem Cell Development, Bagsværd, Denmark / NovaHep AB, Göteborg, Sweden.
    Johansson, Inger
    Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Edsbagge, Josefina
    Takara Bio Europe AB (Former Cellectis AB/Cellartis AB), Göteborg, Sweden.
    High Content Analysis of Human Pluripotent Stem Cell Derived Hepatocytes Reveals Drug Induced Steatosis and Phospholipidosis2016In: Stem Cells International, ISSN 1687-9678, Vol. 2016, article id 2475631Article in journal (Refereed)
    Abstract [en]

    Hepatotoxicity is one of the most cited reasons for withdrawal of approved drugs from the market. The use of nonclinically relevant in vitro and in vivo testing systems contributes to the high attrition rates. Recent advances in differentiating human induced pluripotent stem cells (hiPSCs) into pure cultures of hepatocyte-like cells expressing functional drug metabolizing enzymes open up possibilities for novel, more relevant human cell based toxicity models. The present study aimed to investigate the use of hiPSC derived hepatocytes for conducting mechanistic toxicity testing by image based high content analysis (HCA). The hiPSC derived hepatocytes were exposed to drugs known to cause hepatotoxicity through steatosis and phospholipidosis, measuring several endpoints representing different mechanisms involved in drug induced hepatotoxicity. The hiPSC derived hepatocytes were benchmarked to the HepG2 cell line and generated robust HCA data with low imprecision between plates and batches. The different parameters measured were detected at subcytotoxic concentrations and the order of which the compounds were categorized (as severe, moderate, mild, or nontoxic) based on the degree of injury at isomolar concentration corresponded to previously published data. Taken together, the present study shows how hiPSC derived hepatocytes can be used as a platform for screening drug induced hepatotoxicity by HCA.

  • 17.
    Sartipy, Peter
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Holmgren, Gustav
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Andersson, Christian
    Takara Bio, Gothenburg, Sweden.
    Lindahl, Anders
    University of Gothenburg, Sweden.
    Visual integration of multiple omics data from human pluripotent stem cell-derived cardiomyocytes2017Conference paper (Refereed)
  • 18.
    Stahel, Anette
    University of Skövde, School of Life Sciences.
    24,25(OH)2D3 and Regulation of Catalase Activity in LNCaP Prostate Cancer2007Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The vitamin D metabolite 1,25(OH)2D3 has long been known to inhibit growth of prostate cancer cells and this has been attributed to a VDR-mediated pathway controlling target gene expression, resulting in cell cycle arrest, apoptosis and differentiation. New research has shown that another vitamin D metabolite, 24,25(OH)2D3, inhibits proliferation of prostate cancer cells as well, more specifically, cells of the line LNCaP. It is not clear exactly how 24,25(OH)2D3 exerts this cancer growth inhibition but it has been shown that it is to some extent regulated via G protein coupled signalling pathways. Catalase is a haem-containing redox enzyme found in the majority of animal cells, plant cells and aerobic microorganisms. This enzyme is very important because it prevents excessive accumulation of the strongly oxidizing agent H2O2 which otherwise can do damage to the cells. Because of this preventive effect of catalase, important cellular processes which generate H2O2 as by-product can proceed safely. Biochemical analysis of catalase has shown that it binds endogenously to 24,25(OH)2D3. The fact that 24,25(OH)2D3 has anti-proliferative effects on prostate cancer cells combined with the fact that it binds to catalase generates the hypothesis that this binding interferes with the essential task of catalase to keep the cell free from accumulation of destructive H2O2, and by means of this interference induces apoptosis. Finding out about the cancer growth inhibiting mechanism behind each vitamin D metabolite is important and may be a lead in the search for a new, better treatment of prostate cancer. The specific aim of this project was to study if and in what way 24,25(OH)2D3 affects the enzymatic activity of catalase in LNCaP cells and to do this with dose and time responses in focus. In this experiment LNCaP cells were incubated for 48 hours together with 24,25(OH)2D3 in five different concentrations, then a catalase assay was performed on the cells including fluorescence-mediated measuring of catalase activity in both treated and untreated cells. The analysis of the result values showed that regardless of dose or time, 24,25(OH)2D3 has no statistically significant effect on catalase activity in cells of the line LNCaP.

  • 19.
    Starokozhko, Viktoriia
    et al.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
    Vatakuti, Suresh
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
    Schievink, Bauke H.
    Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Merema, Marjolijn T.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
    Asplund, Annika
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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, Groningen, The Netherlands.
    Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days2017In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 5, p. 2079-2092Article in journal (Refereed)
    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.

  • 20.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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 Pathways2014In: The Orthopaedic Journal of Sports Medicine, ISSN 2325-9671, Vol. 2, no 9, p. 1-14, article id 2325967114550781Article in journal (Refereed)
    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.

  • 21.
    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.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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 chondrocytes2014In: American Journal of Veterinary Research, ISSN 0002-9645, E-ISSN 1943-5681, Vol. 75, no 2, p. 132-140Article in journal (Refereed)
    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.

  • 22.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Explore transcription factor profiles in human pluripotent stem cells2014In: 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, p. 197-202Conference paper (Refereed)
    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.

  • 23.
    Synnergren, Jane
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    MicroRNA regulatory network involved in impaired functionality in cardiomyocytes derived from human embryonic stem cells2012In: 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, p. 133-138Conference paper (Refereed)
    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.

  • 24.
    Synnergren, Jane
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Drowley, Lauren
    Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Plowright, Alleyn T.
    Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Brolén, Gabriella
    Discovery Sciences, AstraZeneca Gothenburg, Mölndal, Sweden.
    Goumans, Marie-Josè
    Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
    Gittenberger-de Groot, Adriana C.
    Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Cardiovascular and Metabolic Disease Global Medicines Development Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Wang, Qing-Dong
    Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitors and hiPSC-derived cardiac progenitors2016In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 48, no 11, p. 771-784Article in journal (Refereed)
    Abstract [en]

    Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitor cells and hiPSC-derived cardiac progenitor cells: effects of hypoxic vs normoxic culture conditions.

  • 25.
    Synnergren, Jane Marie
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Ameén, Caroline
    Takara Bio Europe, Gothenburg, Sweden.
    Åkesson, Karolina
    Takara Bio Europe, Gothenburg, Sweden.
    Karlsson, Alexander
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Riveiro, Maria
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Andersson, Christian X.
    Takara Bio Europe, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Transcriptional profiling of human embryonic stem cells during mesodermal- and cardiac differentiation2016Conference paper (Refereed)
  • 26.
    Ulvestad, Maria
    et al.
    AstraZeneca, Sweden / Cellectis AB, Sweden / University of Oslo, Norway.
    Nordell, Pär
    AstraZeneca, Sweden.
    Asplund, Annika
    Cellectis AB, Sweden.
    Rehnström, Marie
    Cellectis AB, Sweden.
    Jacobsson, Susanna
    Cellectis AB, Sweden.
    Holmgren, Gustav
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Sweden / Sahlgrenska University Hospital, Sweden.
    Davidson, Lindsay
    University of Dundee, Scotland.
    Brolén, Gabriella
    AstraZeneca, Sweden.
    Edsbagge, Josefina
    Cellectis AB, Sweden.
    Björquist, Petter
    Cellectis AB, Sweden.
    Küppers-Munther, Barbara
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Sweden.
    Andersson, Tommy B.
    AstraZeneca, Sweden / Karolinska Institute, Sweden.
    Drug metabolizing enzyme and transporter protein profiles of hepatocytes derived from human embryonic and induced pluripotent stem cells2013In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 86, no 5, p. 691-702Article in journal (Refereed)
    Abstract [en]

    Human embryonic and induced pluripotent stem cell-derived hepatocytes (hESC-Hep and hiPSC-Hep) have the potential to provide relevant human in vitro model systems for toxicity testing and drug discovery studies. In this study, the expression and function of important drug metabolizing cytochrome P450 (CYP) enzymes and transporter proteins in hESC-Hep and hiPSC-Hep were compared to cryopreserved human primary hepatocytes (hphep) and HepG2 cells. Overall, CYP activities in hESC-Hep and hiPSC-Hep were much lower than in hphep cultured for 4 h, but CYP1A and 3A activities were comparable to levels in hphep cultured for 48 h (CYP1A: 35% and 26% of 48 h hphep, respectively; CYP3A: 80% and 440% of 48 h hphep, respectively). Importantly, in hESC-Hep and hiPSC-Hep, CYP activities were stable or increasing for at least one week in culture which was in contrast to the rapid loss of CYP activities in cultured hphep between 4 and 48 h after plating. With regard to transporters, in hESC-Hep and hiPSC-Hep, pronounced NTCP activity (17% and 29% of 4 h hphep, respectively) and moderate BSEP activity (6% and 8% of 4 h hphep, respectively) were observed. Analyses of mRNA expression and immunocytochemistry supported the observed CYP and transporter activities and showed expression of additional CYPs and transporters. In conclusion, the stable expression and function of CYPs and transporters in hESC-Hep and hiPSC-Hep for at least one week opens up the possibility to reproducibly perform long term and extensive studies, e.g. chronic toxicity testing, in a stem cell-derived hepatic system. (C) 2013 Elsevier Inc. All rights reserved.

  • 27.
    Wullimann, David
    University of Skövde, School of Health and Education.
    Discovery of candidate biomarkers for purification of atrial and ventricular cardiomyocytes derived from human pluripotent stemcells: Version 22017Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
  • 28.
    Yewale, Priti Prabhakar
    et al.
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Lokhande, Kiran Bharat
    Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Sridhar, Aishwarya
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Vaishnav, Monika
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Khan, Faisal Ahmad
    The Life Science Centre-Biology, School of Science and Technology, Örebro University, Sweden.
    Mandal, Abul
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Swamy, Kakumani Venkateswara
    Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Jass, Jana
    The Life Science Centre-Biology, School of Science and Technology, Örebro University, Sweden.
    Nawani, Neelu
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Molecular profiling of multidrug-resistant river water isolates: insights into resistance mechanism and potential inhibitors2019In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499Article in journal (Refereed)
    Abstract [en]

    Polluted waters are an important reservoir for antibiotic resistance genes and multidrug-resistant bacteria. This report describes the microbial community, antibiotic resistance genes, and the genetic profile of extended spectrum β-lactamase strains isolated from rivers at, Pune, India. ESBL-producing bacteria isolated from diverse river water catchments running through Pune City were characterized for their antibiotic resistance. The microbial community and types of genes which confer antibiotic resistance were identified followed by the isolation of antibiotic-resistant bacteria on selective media and their genome analysis. Four representative isolates were sequenced using next generation sequencing for genomic analysis. They were identified as Pseudomonas aeruginosa, Escherichia coli, and two isolates were Enterobacter cloacae. The genes associated with the multidrug efflux pumps, such as tolC, macA, macB, adeL, and rosB, were detected in the isolates. As MacAB-TolC is an ABC type efflux pump responsible for conferring resistance in bacteria to several antibiotics, potential efflux pump inhibitors were identified by molecular docking. The homology model of their MacB protein with that from Escherichia coli K12 demonstrated structural changes in different motifs of MacB. Molecular docking of reported efflux pump inhibitors revealed the highest binding affinity of compound MC207-110 against MacB. It also details the potential efflux pump inhibitors that can serve as possible drug targets in drug development and discovery. 

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