Abstract:
BACKGROUND & AIMS:Hepatocytes differentiated from human embryonic stem cells (hESCs) have the potential to overcome the shortage of primary hepatocytes for clinical use and drug development. Many strategies for this process have been reported, but the functionality of the resulting cells is incomplete. We hypothesize that the functionality of hPSC-derived hepatocytes might be improved by making the differentiation method more similar to normal in vivo hepatic development. METHODS:We tested combinations of growth factors and small molecules targeting candidate signaling pathways culled from the literature to identify optimal conditions for differentiation of hESCs to hepatocytes, using qRT-PCR for stage-specific markers to identify the best conditions. Immunocytochemistry was then used to validate the selected conditions. Finally, induction of expression of metabolic enzymes in terminally differentiated cells was used to assess the functionality of the hESC-derived hepatocytes. RESULTS:Optimal differentiation of hESCs was attained using a 5-stage protocol. After initial induction of definitive endoderm (stage 1), we showed that inhibition of the WNT/β-catenin pathway during the 2nd and 3rd stages of differentiation was required to specify first posterior foregut, and then hepatic gut cells. In contrast, during the 4th stage of differentiation, we found that activation of the WNT/β-catenin pathway allowed generation of proliferative bipotent hepatoblasts, which then were efficiently differentiated into hepatocytes in the 5th stage by dual inhibition of TGF-β and NOTCH signaling. CONCLUSION:Here, we show that stage-specific regulation of the WNT/β-catenin pathway results in improved differentiation of hESCs to functional hepatocytes.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Touboul T,Chen S,To CC,Mora-Castilla S,Sabatini K,Tukey RH,Laurent LCdoi
10.1016/j.jhep.2016.02.028subject
Has Abstractpub_date
2016-06-01 00:00:00pages
1315-26issue
6eissn
0168-8278issn
1600-0641pii
S0168-8278(16)00162-8journal_volume
64pub_type
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abstract:BACKGROUND & AIMS:Weak hepatitis C virus (HCV) specific immunity in peripheral blood has been shown to be partially controlled by regulatory T cells (Treg). However, little is known about Treg present in livers of HCV-infected patients, their association with clinical parameters, and immunopathology resulting in diseas...
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pub_type: 评论,杂志文章
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更新日期:2004-01-01 00:00:00
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更新日期:2000-01-01 00:00:00
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更新日期:2021-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0168-8278(00)80280-9
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doi:10.1016/j.jhep.2013.06.019
更新日期:2013-11-01 00:00:00
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.03.025
更新日期:2004-07-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.07.039
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pub_type: 杂志文章
doi:10.1016/j.jhep.2010.10.025
更新日期:2011-07-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.03.026
更新日期:2009-09-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2008.02.021
更新日期:2008-07-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/0168-8278(91)90009-z
更新日期:1991-01-01 00:00:00
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journal_title:Journal of hepatology
pub_type:
doi:10.1016/j.jhep.2007.09.003
更新日期:2007-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.jhep.2010.04.009
更新日期:2010-09-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0168-8278(86)80151-9
更新日期:1986-01-01 00:00:00