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  • 1.
    Asp, Julia
    et al.
    Univ Gothenburg, Dept Clin Chem & Transfus Med, Inst Biomed, Sahlgrenska Acad, S-41345 Gothenburg, Sweden .
    Synnergren, Jane
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Jonsson, Marianne
    Univ Gothenburg, Dept Clin Chem & Transfus Med, Inst Biomed, Sahlgrenska Acad, S-41345 Gothenburg, Sweden .
    Dellgren, Goran
    Univ Gothenburg, Dept Mol & Clin Med, Sahlgrenska Acad, S-41345 Gothenburg, Sweden / Sahlgrens Univ Hosp, Dept Cardiothorac Surg, Gothenburg, Sweden.
    Jeppsson, Anders
    Univ Gothenburg, Dept Mol & Clin Med, Sahlgrenska Acad, S-41345 Gothenburg, Sweden / Sahlgrens Univ Hosp, Dept Cardiothorac Surg, Gothenburg, Sweden.
    Comparison of human cardiac gene expression profiles in paired samples of right atrium and left ventricle collected in vivo2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 1, 89-98 p.Article in journal (Refereed)
    Abstract [en]

    Asp J, Synnergren J, Jonsson M, Dellgren G, Jeppsson A. Comparison of human cardiac gene expression profiles in paired samples of right atrium and left ventricle collected in vivo. Physiol Genomics 44: 89-98, 2012. First published November 15, 2011; doi: 10.1152/physiolgenomics.00137.2011.-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.
    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
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    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 Applications2010In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 16, no 7, 2161-2182 p.Article in journal (Refereed)
    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.

  • 3.
    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, 430-446 p.Article 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.

  • 4.
    Ghosheh, Nidal
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Olsson, Björn
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines2016In: Stem Cells International, ISSN 1687-9678, Vol. 2016, 8648356Article in journal (Refereed)
    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.

  • 5.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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 cells2015In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 63, no 4, 934-942 p.Article in journal (Refereed)
    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.

  • 6.
    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, 232-239 p.Article 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.

  • 7.
    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, 1401-1406 p.Article 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.

  • 8.
    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, 26-34 p.Article 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.

  • 9.
    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, 102-111 p.Article 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.

  • 10.
    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
    University of Skövde, Department of Natural Sciences. University of Skövde, School of Bioscience.
    Becker, Bruno
    Department of Psychiatry and Neurochemistry, Sahlgrenska University Hospital, Mölndal, Sweden.
    Towards Creating the Perfect In Vitro Cell Model2016In: Stem Cells International, ISSN 1687-9678, Vol. 2016, 3459730Article in journal (Refereed)
  • 11.
    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
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    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 tissue2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 424, no 2, 327-330 p.Article in journal (Refereed)
    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.

  • 12.
    Riveiro, Maria
    et al.
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Lebram, Mikael
    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. Astra Zeneca, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Interactive visualization of large-scale gene expression data2016In: 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, 348-354 p.Conference paper (Refereed)
    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.

  • 13.
    Sartipy, P.
    et al.
    Cellartis AB, Arvid Wallgrens Backe 20, SE-413 46 Göteborg, Sweden.
    Olsson, Björn
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Hyllner, J.
    Cellartis AB, Arvid Wallgrens Backe 20, SE-413 46 Göteborg, Sweden.
    Synnergren, Jane
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Regulation of 'stemness' and stem cell differentiation by microRNAs2009In: IDrugs. The Investigational Drugs Journal, ISSN 1369-7056, E-ISSN 2040-3410, Vol. 12, no 8, 492-496 p.Article, review/survey (Refereed)
    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.

  • 14.
    Sivertsson, Louise
    et al.
    Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Synnergren, Jane
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    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 bioreactor2013In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 22, no 4, 581-594 p.Article in journal (Refereed)
    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. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

  • 15.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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 patients2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 59, 1-9 p.Article in journal (Refereed)
    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.

  • 16.
    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, 2079-2092 p.Article 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.

  • 17.
    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: Orthopaedic journal of sports medicine, ISSN 2325-9671, Vol. 2, no 9, 1-14 p., 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.

  • 18.
    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, 132-140 p.Article 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.

  • 19.
    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, 197-202 p.Conference 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.

  • 20.
    Synnergren, Jane
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Identification of miRNAs in Control of Aberrant Gene Transcription in Human Pluripotent Stem Cell Derived Hepatocytes2013In: 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, 11-16 p.Conference paper (Refereed)
  • 21.
    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, 133-138 p.Conference 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.

  • 22.
    Synnergren, Jane
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Transcriptional profiling of human embryonic stem cells and their functional derivatives2010Doctoral thesis, comprehensive summary (Other academic)
    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. 

  • 23.
    Synnergren, Jane
    University of Skövde, School of Humanities and Informatics.
    Understanding the differentiation of human embryonic stem cells2006Report (Other academic)
    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.

  • 24.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences.
    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
    University of Skövde, School of Life Sciences.
    Nelson, Deirdre
    GE Global Res Ctr, Moscow 123098, Russia.
    Abbot, Stewart
    GE Global Res Ctr, Moscow 123098, Russia.
    Olsson, Björn
    University of Skövde, School of Life Sciences.
    Sartipy, Peter
    Celllartis AB, SE-43146 Gothenburg, Sweden.
    Cardiomyogenic gene expression profiling of differentiating human embryonic stem cells2008In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 134, no 1-2, 162-170 p.Article in journal (Refereed)
    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.

  • 25.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital.
    Ameen, Caroline
    Cellartis, Göteborg, Sweden.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis, Göteborg, Sweden.
    Global transcriptional profiling reveals similarities and differences between human stem cell-derived cardiomyocyte clusters and heart tissue2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 4, 245-258 p.Article in journal (Refereed)
    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.

  • 26.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Améen, Caroline
    Cellartis, Gothenburg, Sweden.
    Lindahl, Anders
    Dept of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital, Sweden.
    Olsson, Björn
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis, Gothenburg, Sweden .
    Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue2011In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 10, 581-594 p.Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue-like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation.

  • 27.
    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, 771-784 p.Article 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.

  • 28.
    Synnergren, Jane
    et al.
    University of Skövde, School of Humanities and Informatics.
    Gamalielsson, Jonas
    University of Skövde, School of Humanities and Informatics.
    Björn, Olsson
    University of Skövde, School of Humanities and Informatics.
    Mapping of the JDL data fusion model to bioinformatics2007In: Systems, Man and Cybernetics, 2007. ISIC. IEEE International Conference on, IEEE Press, 2007, 2969-2974 p.Conference paper (Refereed)
    Abstract [en]

    Information fusion (IF) is a rapidly developing research area which concerns the study of methods to combine the analysis of different data sources in such a way that it increases our understanding of the system under study. The synergistic effects of using multiple data sources and repeatedly updating the model when new data is available, increases the reliability of the model and makes it better suited for e.g. decision support. However, information fusion is a challenging task and more research is needed on how to best integrate data of heterogeneous types and structures in a combined analysis. Initially, IF was mainly used in military contexts, but the algorithms developed are likely to be useful in many other domains. The JDL Data Fusion Model was developed to facilitate IF processes. Here, we investigate its applicability for bioinformatics problems in general and we present an example where it is applied in a study of stem cell differentiation.

  • 29.
    Synnergren, Jane
    et al.
    University of Skövde, School of Humanities and Informatics.
    Giesler, Therese L.
    GE Healthcare, Piscataway, NJ, United States.
    Adak, Sudeshna
    GE John F. Welch Technology Centre Export Promotion Industrial Park, Bangalore, India.
    Tandon, Reeti
    GE John F. Welch Technology Centre Export Promotion Industrial Park, Bangalore, India.
    Noaksson, Karin
    Cellartis AB, Göteborg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Nelson, Deirdre
    GE Global Research Center, Niskayuna, NY, United States.
    Olsson, Björn
    University of Skövde, School of Humanities and Informatics.
    Englund, Mikael C. O.
    Cellartis AB, Göteborg, Sweden.
    Abbott, Stewart
    GE Global Research Center, Niskayuna, NY, United States.
    Sartipy, Peter
    Cellartis AB, Göteborg, Sweden / Cellartis AB, Arvid Wallgrens Backe 20, SE-41346 Göteborg, Sweden.
    Differentiating human embryonic stem cells express a unique housekeeping gene signature2007In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 25, no 2, 473-480 p.Article in journal (Refereed)
    Abstract [en]

    Housekeeping genes (HKGs) are involved in basic functions needed for the sustenance of the cell and are assumed to be constitutively expressed at a constant level. Based on these features, HKGs are frequently used for normalization of gene expression data. In the present study, we used the CodeLink Gene Expression Bioarray system to interrogate changes in gene expression occurring during differentiation of human ESCs (hESCs). Notably, in the three hESC lines used for the study, we observed that the RNA levels of 56 frequently used HKGs varied to a degree that rendered them inappropriate as reference genes. Therefore, we defined a novel set of HKGs specifically for hESCs. Here we present a comprehensive list of 292 genes that are stably expressed (coefficient of variation <20%) in differentiating hESCs. These genes were further grouped into high-, medium-, and low-expressed genes. The expression patterns of these novel HKGs show very little overlap with results obtained from somatic cells and tissues. We further explored the stability of this novel set of HKGs in independent, publicly available gene expression data from hESCs and observed substantial similarities with our results. Gene expression was confirmed by real-time quantitative polymerase chain reaction analysis. Taken together, these results suggest that differentiating hESCs have a unique HKG signature and underscore the necessity to validate the expression profiles of putative HKGs. In addition, this novel set of HKGs can preferentially be used as controls in gene expression analyses of differentiating hESCs.

  • 30.
    Synnergren, Jane
    et al.
    University of Skövde, School of Humanities and Informatics.
    Giesler, Therese L
    Sudeshna, Adak
    Tandon, Reeti
    Noaksson, Karin
    Lindahl, Anders
    Nilsson, Patric
    Nelson, Deidre
    Olsson, Björn
    University of Skövde, School of Humanities and Informatics.
    Englund, Mikael C O
    Abbot, Stewart
    Sartipy, Peter
    Differentiating human embryonic stem cells express a unique housekeeping gene signature2006In: 4th ISSCR Annual Meeting, 2006Conference paper (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESCs) represent populations of pluripotent undifferentiated cells with unlimited replication capacity which can be coaxed to differentiate into a variety of specialized cells. As a result, there is great hope that hESCs will be extremely useful by providing platforms for various in vitro applications (e.g. in drug discovery) as well as for future use of hESCs and their differentiated progeny in cell replacement therapies. In order to realize the potential of hESCs, it is necessary to gain much deeper knowledge about the processes that govern differentiation of these cells.

    In recent years, significant progress towards understanding cellular differentiation has been fuelled, in part, by studying gene expression using microarrays. In this large scale studies, statistical methods are used to normalize the gene expression data and render comparisons between different samples. In lower throughput analyses, RNA levels in hESCs are also measured using RT-PCR requiring normalization of the gene expression data to adequately correct for inter-sample variation. In general, investigators have used the traditional housekeeping genes (HKGs) (e.g. GAPDH, b-tubulin, b-actin) in studies of hESCs. HKGs are involved in basic functions needed for the sustenance of the cell and are assumed to be constitutively expressed at a constant level. Based on these features, HKGs are frequently used for normalization of gene expression data. However, it is well known that the expression of several of these genes vary considerably in adult tissues and their suitability as HKGs in hESCs remains to be proven. In this regard, the RNA levels of HPRT and b-tubulin were shown to vary substantially in differentiating mouse ESCs.

    In the present study, we used the CodeLinkTM Gene Expression Bioarray system to interrogate changes in gene expression occurring during differentiation of hESCs. Notably, in the three hESC lines used for the study, we observed that the RNA levels of 56 frequently used HKGs varied to a degree that rendered them inappropriate as reference genes. Therefore, we defined a novel set of HKGs specifically for hESCs. Here we present a comprehensive list of 292 genes that are stably expressed (coefficient of variation<20%) in differentiating hESCs. These genes were further grouped into high, medium, and low expressed genes. The expression patterns of these novel HKGs show very little overlap with results obtained from somatic cells and tissues. We further explored the stability of this novel set of HKGs in independent, publicly available gene expression data from hESCs and observed substantial similarities in terms of stably expressed genes. Taken together, these results suggest that hESCs have a unique HKG signature and underscore the necessity to validate the expression profiles of putative HKGs. In addition, the novel set of identified HKGs can preferentially be used as controls in gene expression analyses of differentiating hESCs.

  • 31.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Heins, Nico
    Cellartis AB, Göteborg.
    Brolén, Gabriella
    Cellartis AB, Göteborg.
    Eriksson, Gustav
    Cellartis AB, Göteborg.
    Lindahl, Anders
    Sahlgrenska University Hospital.
    Hyllner, Johan
    Cellartis AB, Göteborg.
    Olsson, Björn
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis AB, Göteborg.
    Björnquist, Petter
    Cellartis AB, Göteborg.
    Transcriptional profiling of human embryonic stem cells differentiating to definitive and primitive endoderm and further towards the hepatic lineage2010In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 19, no 7, 961-978 p.Article in journal (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESC) can differentiate into a variety of specialized cell types, and they constitute a useful model system to study embryonic development in vitro. In order to fully utilize the potential of these cells, the mechanisms that regulate the developmental processes of specific lineage differentiation need to be better defined. The aim of this study was to explore the molecular program involved in the differentiation of hESC towards definitive endoderm (DE) and further into the hepatic lineage, and to compare that to primitive endoderm (PrE) differentiation. To that end, we applied two protocols, a specific DE differentiation protocol and an intrinsic differentiation protocol that mainly mediates PrE formation. We collected hESC, hESC-derived DE, DE-derived hepatocyte-progenitors (DE-Prog), DE-derived hepatocyte-like cells (DE-Hep), and the corresponding PrE-derivatives. The samples were analyzed using microarrays, and we identified sets of genes which were exclusively up-regulated in DE-derivatives (compared to PrE-derivatives) at discrete developmental stages. We also investigated known protein interactions among the set of up-regulated genes in DE-Hep. The results demonstrate important differences between DE- and PrE-differentiation on the transcriptional level. In particular, our results identify a unique molecular program, exclusively activated during development of DE and the subsequent differentiation of DE towards the hepatic lineage. We identified key-genes and pathways of potential importance for future efforts to improve hepatic differentiation from hESC. These results reveal new opportunities for rational design of specific interventions with the purpose of generating enriched populations of DE derivatives, including functional hepatocytes.

  • 32.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Olsson, Björn
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Gamalielsson, Jonas
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    A Data Integration Method for Exploring Gene Regulatory Mechanisms2008In: Conference on Information and Knowledge Management: Proceedings of the 2nd international workshop on Data and text mining in bioinformatics, ACM Press, 2008, 81-84 p.Conference paper (Refereed)
    Abstract [en]

    Systems biology aims to understand the behavior of and interaction between various components of the living cell, such as genes, proteins, and metabolites. A large number of components are involved in these complex systems and the diversity of relationships between the components can be overwhelming, and there is therefore a need for analysis methods incorporating data integration. We here present a method for exploring gene regulatory mechanisms which integrates various types of data to assist the identification of important components in gene regulation mechanisms. By first analyzing gene expression data, a set of differentially expressed genes is selected. These genes are then further investigated by combining various types of biological information, such as clustering results, promoter sequences, binding sites, transcription factors and other previously published information regarding the selected genes. Inspired by Information Fusion research, we also mapped functions of the proposed method to the well-known OODA-model to facilitate application of this data integration method in other research communities. We have successfully applied the method to genes identified as differentially expressed in human embryonic stem cells at different stages of differentiation towards cardiac cells. We identified 15 novel motifs that may represent important binding sites in the cardiac cell linage.

  • 33.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Olsson, Björn
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Gamalielsson, Jonas
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Classification of information fusion methods in systems biology2009In: In Silico Biology, ISSN 1386-6338, Vol. 9, no 3, 65-76 p.Article, review/survey (Refereed)
    Abstract [en]

    Biological systems are extremely complex and often involve thousands of interacting components. Despite all efforts, many complex biological systems are still poorly understood. However, over the past few years high-throughput technologies have generated large amounts of biological data, now requiring advanced bioinformatic algorithms for interpretation into valuable biological information. Due to these high-throughput technologies, the study of biological systems has evolved from focusing on single components (e.g. genes) to encompassing large sets of components (e.g. all genes in an entire genome), with the aim to elucidate their interdependences in various biological processes. In addition, there is also an increasing need for integrative analysis, where knowledge about the biological system is derived by data fusion, using heterogeneous data sets as input. We here review representative examples of bioinformatic methods for fusion-oriented interpretation of multiple heterogeneous biological data, and propose a classification into three categories of tasks that they address: data extraction, data integration and data fusion. The aim of this classification is to facilitate the exchange of methods between systems biology and other information fusion application areas.

  • 34.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis AB, Sweden.
    Microarray Analysis of Undifferentiated and Differentiated Human Pluripotent Stem Cells2011In: Methodological Advances in the Culture, Manipulation and Utilization of Embryonic Stem Cells for Basic and Practical Applications / [ed] Craig Atwood, Rijeka, Croatia: INTECH, 2011, 343-366 p.Chapter in book (Refereed)
  • 35.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Sartipy, Peter
    Cellartis AB, Sweden.
    Transcriptional analysis of messenger-RNA and micro-RNA array data reveals global negative correlation in human stem cell derived cardiomyocyte clusters2012In: 4th International Conference on Bioinformatics and Computational Biology / [ed] F. Saeed H. Al-Mubaid, Curran Associates, Inc., 2012, 178-183 p.Conference paper (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are small non-coding molecules that have been shown to play key roles in regulating cellular development and to be involved in various diseases. By interfering with their target mRNAs, these molecules inhibit the expression of proteins, either by de-stabilizing the messenger RNA (mRNA) molecule or by preventing its translation. Each miRNA can target hundreds of mRNAs, and one mRNA can be targeted by several miRNAs.This makes it extremely complex to determine the regulatory functions of specific miRNAs in the transcription and translation processes. However, important advancements in microarray technology have made large scale monitoring of miRNA expression possible. This opens the possibility to move from studies of single molecules to studies of complex molecular processes, pathways, and biological systems. Recent studies have indicated important roles for miRNAs in stem cell differentiation in general and in cardiac development in particular. This paper presents a global transcriptional study where putativecorrelation between miRNA and mRNA expression in fetal- and adult heart tissues samples and in clusters of cardiomyocytes derived from human embryonic stem cells (hESCs) were investigated. Target genes of miRNAs expressed in cardiac tissue have been predicted and their transcriptional profiles investigated in tissue specimen. By using a statistical algorithm, up- and down-regulated miRNAs and mRNAs have been identified in four different cardiac related samples. In total, 17 cardiac related miRNAs have been analyzed and for each of these, clusters of negatively correlated target genes were identified. This supports the hypothesis that sets of miRNAs play an important role in modulating the expression of genes, which are important for cardiac development. Interestingly, the results from this study also indicate a global negative correlation between miRNA expression and mRNA expression, which previously has not been reported.

  • 36.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences.
    Åkesson, Karolina
    Cellartis AB, Gothenburg, Sweden.
    Dahlenborg, Kerstin
    Cellartis AB, Gothenburg, Sweden.
    Vidarsson, Hilmar
    Cellartis AB, Gothenburg, Sweden.
    Ameen, Caroline
    Cellartis AB, Gothenburg, Sweden.
    Steel, Daniella
    Cellartis AB, Gothenburg, Sweden.
    Lindahl, Anders
    Sahlgrens Univ Hosp, Dept Clin Chem Transfus Med, S-41345 Gothenburg, Sweden.
    Olsson, Björn
    University of Skövde, School of Life Sciences.
    Sartipy, Peter
    Cellartis AB, Gothenburg, Sweden.
    Molecular signature of cardiomyocyte clusters derived from human embryonic stem cells2008In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 26, no 7, 1831-1840 p.Article in journal (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESCs) can differentiate in vitro into spontaneously contracting cardiomyocytes (CMs). These cells may prove extremely useful for various applications in basic research, drug discovery, and regenerative medicine. To fully use the potential of the cells, they need to be extensively characterized, and the regulatory mechanisms that control hESC differentiation toward the cardiac lineage need to be better defined. In this study, we used microarrays to analyze, for the first time, the global gene expression profile of isolated hESC-derived CM clusters. By comparing the clusters with undifferentiated hESCs and using stringent selection criteria, we identified 530 upregulated and 40 downregulated genes in the contracting clusters. To further characterize the family of upregulated genes in the hESC-derived CM clusters, the genes were classified according to their Gene Ontology annotation. The results indicate that the hESC-derived CM clusters display high similarities, on a molecular level, to human heart tissue. Moreover, using the family of upregulated genes, we created protein interaction maps that revealed topological characteristics. We also searched for cellular pathways among the upregulated genes in the hESC-derived CM clusters and identified eight significantly upregulated pathways. Real-time quantitative polymerase chain reaction and immunohistochemical analysis confirmed the expression of a subset of the genes identified by the microarrays. Taken together, the results presented here provide a molecular signature of hESC-derived CM clusters and further our understanding of the biological processes that are active in these cells.

  • 37.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Özdogan, Alper
    Yildiz Technical University, Turkey.
    Olsson, Björn
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Sartipy, Peter
    Cellartis AB, Göteborg, Sweden.
    Clustering micro-RNA array data using an information fusion based approach with multiple types of input data2010In: Proceedings of the ISCA 2nd International Conference on Bioinformatics and Computational Biology, BICoB-2010, March 24-26, 2010, Sheraton Waikiki Hotel, Honolulu, Hawaii, USA / [ed] Hisham Al-Mubaid, International Society for Computers and Their Applications , 2010, 151-158 p.Conference paper (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are small non-coding molecules that have been shown to play key roles in regulating cellular development and to be involved in various diseases. By interfering with their target mRNAs, these molecules inhibit the expression of proteins, either by destabilizing the mRNA molecule or by preventing its translation. It has been suggested that each miRNA can target hundreds of mRNAs, and that one mRNA can be targeted by several miRNAs. This makes it extremely complex to determine the roles of specific miRNAs in the regulation of translation of mRNA. Recent advancements in microarray technology have made large-scale monitoring of miRNA expression possible. However, the size and complexity of these data sets make them challenging to analyze, and improved algorithms are therefore required to facilitate the analysis. In this paper, we present a novel clustering algorithm that uses an Information Fusion (IF) approach to cluster miRNA data, allowing for multiple types of input data to guide the clustering. For evaluation of the algorithm, we used miRNA expression data from human embryonic stem cells and cardiomyocyte-like cells derived thereof. Clusters obtained when using the multiple input data approach were compared to those generated when using only the expression data. Our results show that it is beneficial to include various types of genomic data as input to the clustering process, since it results in clusters of increased biological relevance.

  • 38.
    Ulfenborg, Benjamin
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    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.
    Améen, Caroline
    Takara Bio Europe AB, Gothenburg, Sweden.
    Åkesson, Karolina
    Takara Bio Europe AB, Gothenburg, Sweden.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    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, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    A data analysis framework for biomedical big data: Application on mesoderm differentiation of human pluripotent stem cells2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, e0179613Article in journal (Refereed)
    Abstract [en]

    The development of high-throughput biomolecular technologies has resulted in generation of vast omics data at an unprecedented rate. This is transforming biomedical research into a big data discipline, where the main challenges relate to the analysis and interpretation of data into new biological knowledge. The aim of this study was to develop a framework for biomedical big data analytics, and apply it for analyzing transcriptomics time series data from early differentiation of human pluripotent stem cells towards the mesoderm and cardiac lineages. To this end, transcriptome profiling by microarray was performed on differentiating human pluripotent stem cells sampled at eleven consecutive days. The gene expression data was analyzed using the five-stage analysis framework proposed in this study, including data preparation, exploratory data analysis, confirmatory analysis, biological knowledge discovery, and visualization of the results. Clustering analysis revealed several distinct expression profiles during differentiation. Genes with an early transient response were strongly related to embryonic-and mesendoderm development, for example CER1 and NODAL. Pluripotency genes, such as NANOG and SOX2, exhibited substantial downregulation shortly after onset of differentiation. Rapid induction of genes related to metal ion response, cardiac tissue development, and muscle contraction were observed around day five and six. Several transcription factors were identified as potential regulators of these processes, e.g. POU1F1, TCF4 and TBP for muscle contraction genes. Pathway analysis revealed temporal activity of several signaling pathways, for example the inhibition of WNT signaling on day 2 and its reactivation on day 4. This study provides a comprehensive characterization of biological events and key regulators of the early differentiation of human pluripotent stem cells towards the mesoderm and cardiac lineages. The proposed analysis framework can be used to structure data analysis in future research, both in stem cell differentiation, and more generally, in biomedical big data analytics.

  • 39.
    Yildirimman, Reha
    et al.
    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany .
    Brolén, Gabriella
    Cellartis AB, SE-41346 Gothenburg, Sweden .
    Vilardell, Mireia
    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany .
    Eriksson, Gustav
    Cellartis AB, SE-41346 Gothenburg, Sweden .
    Synnergren, Jane
    University of Skövde, School of Life Sciences.
    Gmuender, Hans
    Genedata AG, CH-4053 Basel, Switzerland .
    Kamburov, Atanas
    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany .
    Ingelman-Sundberg, Magnus
    Karolinska Inst, Dept Physiol & Pharmacol, Pharmacogenet Sect, S-17177 Stockholm, Sweden .
    Castell, Jose
    Univ Valencia, Fac Med, Dept Biochem & Mol Biol, E-46009 Valencia, Spain / Univ Hosp La Fe Valencia, Unit Expt Hepatol, E-46009 Valencia, Spain .
    Lahoz, Agustin
    Univ Hosp La Fe Valencia, Unit Expt Hepatol, E-46009 Valencia, Spain .
    Kleinjans, Jos
    Maastricht Univ, Dept Toxicogen, NL-6229 ER Maastricht, Netherlands.
    van Delft, Joost
    Maastricht Univ, Dept Toxicogen, NL-6229 ER Maastricht, Netherlands.
    Bjorquist, Petter
    Cellartis AB, SE-41346 Gothenburg, Sweden .
    Herwig, Ralf
    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany .
    Human Embryonic Stem Cell Derived Hepatocyte-Like Cells as a Tool for In Vitro Hazard Assessment of Chemical Carcinogenicity2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 124, no 2, 278-290 p.Article in journal (Refereed)
    Abstract [en]

    Hepatocyte-like cells derived from the differentiation of human embryonic stem cells (hES-Hep) have potential to provide a human relevant in vitro test system in which to evaluate the carcinogenic hazard of chemicals. In this study, we have investigated this potential using a panel of 15 chemicals classified as noncarcinogens, genotoxic carcinogens, and nongenotoxic carcinogens and measured whole-genome transcriptome responses with gene expression microarrays. We applied an ANOVA model that identified 592 genes highly discriminative for the panel of chemicals. Supervised classification with these genes achieved a cross-validation accuracy of > 95%. Moreover, the expression of the response genes in hES-Hep was strongly correlated with that in human primary hepatocytes cultured in vitro. In order to infer mechanistic information on the consequences of chemical exposure in hES-Hep, we developed a computational method that measures the responses of biochemical pathways to the panel of treatments and showed that these responses were discriminative for the three toxicity classes and linked to carcinogenesis through p53, mitogen-activated protein kinases, and apoptosis pathway modules. It could further be shown that the discrimination of toxicity classes was improved when analyzing the microarray data at the pathway level. In summary, our results demonstrate, for the first time, the potential of human embryonic stem cell--derived hepatic cells as an in vitro model for hazard assessment of chemical carcinogenesis, although it should be noted that more compounds are needed to test the robustness of the assay.

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