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Cell Rep. 2018 Feb 20;22(8):2190-2205. doi: 10.1016/j.celrep.2018.01.087.

A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells.

Author information

1
Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore. Electronic address: anglt1@gis.a-star.edu.sg.
2
Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore.
3
Human Genetics Group, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore; Cardiovascular Research Institute, National University of Singapore, Singapore 117599, Singapore.
4
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore.
5
Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
6
Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore; School of Engineering, Temasek Polytechnic, Singapore 529757, Singapore.
7
Humanized Mouse Unit, Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
8
Stanford Institute for Stem Cell Biology & Regenerative Medicine, Department of Developmental Biology, Stanford-UC Berkeley Siebel Stem Cell Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
9
Humanized Mouse Unit, Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore; Department of Microbiology, Yong Yoo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
10
Stem Cell & Regenerative Biology Group, Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore. Electronic address: limb1@gis.a-star.edu.sg.

Abstract

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.

KEYWORDS:

efficient differentiation; human liver development; pluripotent stem cells; progenitor; signaling

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