Godoy, Patricio, Schmidt-Heck, Wolfgang, Natarajan, Karthick, Lucendo-Villarin, Baltasar, Szkolnicka, Dagmara ORCID: 0000-0003-1125-3575, Asplund, Annika, Bjorquist, Petter, Widera, Agata, Stober, Regina, Campos, Gisela, Hammad, Seddik ORCID: 0000-0003-0571-4208, Sachinidis, Agapios, Chaudhari, Umesh ORCID: 0000-0002-7743-4371, Damm, Georg, Weiss, Thomas S., Nuessler, Andreas, Synnergren, Jane ORCID: 0000-0003-4697-0590, Edlund, Karolina, Kueppers-Munther, Barbara, Hay, David C. and Hengstler, Jan G. (2015). Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J. Hepatol., 63 (4). S. 934 - 943. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1600-0641

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Abstract

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 14 days 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Godoy, PatricioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt-Heck, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Natarajan, KarthickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lucendo-Villarin, BaltasarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szkolnicka, DagmaraUNSPECIFIEDorcid.org/0000-0003-1125-3575UNSPECIFIED
Asplund, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bjorquist, PetterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Widera, AgataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stober, ReginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campos, GiselaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammad, SeddikUNSPECIFIEDorcid.org/0000-0003-0571-4208UNSPECIFIED
Sachinidis, AgapiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chaudhari, UmeshUNSPECIFIEDorcid.org/0000-0002-7743-4371UNSPECIFIED
Damm, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weiss, Thomas S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuessler, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Synnergren, JaneUNSPECIFIEDorcid.org/0000-0003-4697-0590UNSPECIFIED
Edlund, KarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kueppers-Munther, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hay, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hengstler, Jan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-392102
DOI: 10.1016/j.jhep.2015.05.013
Journal or Publication Title: J. Hepatol.
Volume: 63
Number: 4
Page Range: S. 934 - 943
Date: 2015
Publisher: ELSEVIER SCIENCE BV
Place of Publication: AMSTERDAM
ISSN: 1600-0641
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EXPRESSION; GROWTH; HEPATOTOXICITY; PROLIFERATIONMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/39210

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