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  • Godoy, PatricioIfADo-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 (författare)

Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells

  • Artikel/kapitelEngelska2015

Förlag, utgivningsår, omfång ...

  • Elsevier,2015
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:his-11775
  • https://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-11775URI
  • https://doi.org/10.1016/j.jhep.2015.05.013DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • CC BY 4.0Corrigendum in: Journal of Hepatology, Volume 64, February 2016, Pages 525-526. doi:10.1016/j.jhep.2015.11.003This study was supported by the European Union Seventh Framework Programme (FP7)-Health projects DETECTIVE (EU-project FP7-Health Grant Agreement No. 266838) and NOTOX (EU-project FP7-Health Grant Agreement No. 267038), and the BMBF (German Federal Ministry of Education and Research) project Virtual Liver (0313854). Dr David C. Hay was supported by the UK Regenerative medicine platform (MR/K026666/1 and MR/L022974/1). Mr. Baltasar Lucendo-Villarin and Ms. Dagmara Szkolnicka were funded by MRC PhD studentships.
  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Schmidt-Heck, WolfgangLeibniz Institute for Natural Product Research and Infection Biology eV-Hans-Knöll Institute, Jena, Germany (författare)
  • Natarajan, KarthickUniversity of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany (författare)
  • Lucendo-Villarin, BaltasarMRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom (författare)
  • Szkolnicka, DagmaraMRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom (författare)
  • Asplund, AnnikaHögskolan i Skövde,Institutionen för biovetenskap,Forskningscentrum för Systembiologi,Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden,Bioinformatik, Bioinformatics(Swepub:his)aspa (författare)
  • Björquist, PetterNovaHep AB, Gothenburg, Sweden (författare)
  • Widera, AgataIfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany (författare)
  • Stöber, ReginaIfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany (författare)
  • Campos, GiselaIfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany (författare)
  • Hammad, SeddikIfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany (författare)
  • Sachinidis, AgapiosUniversity of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany (författare)
  • Chaudhari, UmeshUniversity of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany (författare)
  • Damm, GeorgCharité University Medicine Berlin, Department of General-, Visceral- and Transplantation Surgery, Berlin, Germany (författare)
  • Weiss, Thomas S.Center for Liver Cell Research, Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, Regensburg, Germany (författare)
  • Nüssler, AndreasEberhard Karls University Tübingen, BG Trauma Center, Siegfried Weller Institut, Tübingen, Germany (författare)
  • Synnergren, JaneHögskolan i Skövde,Institutionen för biovetenskap,Forskningscentrum för Systembiologi,Bioinformatics(Swepub:his)synj (författare)
  • Edlund, KarolinaIfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany (författare)
  • Küppers-Munther, BarbaraTakara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden (författare)
  • Hay, David C.MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom (författare)
  • Hengstler, Jan G.IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany (författare)
  • 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, ChileLeibniz Institute for Natural Product Research and Infection Biology eV-Hans-Knöll Institute, Jena, Germany (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Journal of Hepatology: Elsevier63:4, s. 934-9420168-82781600-0641

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