A roadmap for human liver differentiation from pluripotent stem cells

How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multipl...

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Main Authors: Ang, Lay Teng, Tan, Antson Kiat Yee, Autio, Matias I., Goh, Su Hua, Choo, Siew Hua, Lee, Kian Leong, Tan, Jianmin, Pan, Bangfen, Lee, Jane Jia Hui, Lum, Jen Jen, Lim, Christina Ying Yan, Yeo, Isabelle Kai Xin, Wong, Chloe Jin Yee, Liu, Min, Oh, Jueween Ling Li, Chia, Cheryl Pei Lynn, Loh, Chet Hong, Chen, Angela, Chen, Qingfeng, Weissman, Irving L., Loh, Kyle M., Lim, Bing
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2018
Subjects:
Online Access:https://hdl.handle.net/10356/87581
http://hdl.handle.net/10220/45438
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Institution: Nanyang Technological University
Language: English
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Summary:How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-β, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3+HNF4A+ human liver bud progenitors and 81.5% ± 3.2% FAH+ hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah−/−Rag2−/−Il2rg−/− mouse model of liver failure.