A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells

• DOI: 10.1016/j.celrep.2018.01.087
• Publication Date: 2018-02-23T15:45:22Z
• Authors: Lay Teng Ang; Antson Kiat Yee Tan; Matias I. Autio; Su Hua Goh; Siew Hua Choo; Kian Leong Lee; Jianmin Tan; Bangfen Pan; Jane Jia Hui Lee; Jen Jen Lum; Christina Ying Ya...; Isabelle Kai Xin Yeo; Chloe Jin Yee Wong; Min Liu; Jueween Ling Li Oh; Cheryl Pei Lynn Chia; Chet Hong Loh; Angela Chen; Qingfeng Chen; Irving L. Weissman; Kyle M. Loh; Bing Lim
• Keywords: Cell fate determination

How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned developmental biology to rapidly reconstitute liver progenitors human pluripotent stem cells (hPSCs). Mapping the formation of multiple lineages revealed how alternate fates (e.g., pancreas intestines) restricted during commitment. Human fate was encoded by combinations inductive repressive extracellular signals at different doses. However, these signaling were temporally re-interpreted: cellular competence respond retinoid, WNT, TGF-β, other sharply changed within 24 hr. Consequently, dynamic manipulation imperative suppress production unwanted cell across six consecutive junctures. This efficiently generated 94.1% ± 7.35% TBX3+HNF4A+ bud 81.5% 3.2% FAH+ hepatocyte-like days 6 18 hPSC differentiation, respectively; latter improved short-term survival in Fah−/−Rag2−/−Il2rg−/− mouse model failure.