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...

Full description

Saved in:
Bibliographic Details
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
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-87581
record_format dspace
spelling sg-ntu-dr.10356-875812023-02-28T17:02:03Z A roadmap for human liver differentiation from pluripotent stem cells 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 School of Biological Sciences Human Liver Development 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 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. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version 2018-08-02T08:27:49Z 2019-12-06T16:44:56Z 2018-08-02T08:27:49Z 2019-12-06T16:44:56Z 2018 Journal Article Ang, L. T., Tan, A. K. Y., Autio, M. I., Goh, S. H., Choo, S. H., Lee, K. L., et al. (2018). A roadmap for human liver differentiation from pluripotent stem cells. Cell Reports, 22(8), 2190-2205. 2211-1247 https://hdl.handle.net/10356/87581 http://hdl.handle.net/10220/45438 10.1016/j.celrep.2018.01.087 en Cell Reports © 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 39 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Human Liver Development
Pluripotent Stem Cells
spellingShingle Human Liver Development
Pluripotent Stem Cells
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
A roadmap for human liver differentiation from pluripotent stem cells
description 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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
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
format Article
author 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
author_sort Ang, Lay Teng
title A roadmap for human liver differentiation from pluripotent stem cells
title_short A roadmap for human liver differentiation from pluripotent stem cells
title_full A roadmap for human liver differentiation from pluripotent stem cells
title_fullStr A roadmap for human liver differentiation from pluripotent stem cells
title_full_unstemmed A roadmap for human liver differentiation from pluripotent stem cells
title_sort roadmap for human liver differentiation from pluripotent stem cells
publishDate 2018
url https://hdl.handle.net/10356/87581
http://hdl.handle.net/10220/45438
_version_ 1759857016151474176