RT Journal Article
SR Electronic
T1 Accelerated human liver progenitor generation from pluripotent stem cells by inhibiting formation of unwanted lineages
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 174698
DO 10.1101/174698
A1 Lay Teng Ang
A1 Antson Kiat Yee Tan
A1 Matias Ilmari Autio
A1 Joanne Su-Hua Goh
A1 Siew Hua Choo
A1 Kian Leong Lee
A1 Jianmin Tan
A1 Bangfen Pan
A1 Jane Jia Hui Lee
A1 Isabelle Kai Xin Yeo
A1 Chloe Jin Yee Wong
A1 Jen Jen Lum
A1 Chet Hong Loh
A1 Ying Yan Lim
A1 Jueween Ling Li Oh
A1 Cheryl Pei Lynn Chia
A1 Angela Chen
A1 Qing Feng Chen
A1 Irving L. Weissman
A1 Kyle M. Loh
A1 Bing Lim
YR 2017
UL http://biorxiv.org/content/early/2017/08/10/174698.abstract
AB Despite decisive progress in differentiating pluripotent stem cells (PSCs) into diverse cell-types, the often-lengthy differentiation and functional immaturity of such cell-types remain pertinent issues. Here we address the first challenge of prolonged differentiation in the generation of hepatocyte-like cells from PSCs. We delineate a roadmap describing the extracellular signals controlling six sequential branching lineage choices leading from pluripotency to endoderm, foregut, and finally, liver progenitors. By blocking formation of unwanted cell-types at each lineage juncture and manipulating temporally-dynamic signals, we accelerated generation of 89.0±3.1% AFP+ human liver bud progenitors and 87.3±9.4% ALBUMIN+ hepatocyte-like cells by days 6 and 18 of PSC differentiation, respectively. 81.5±3.2% of hepatocyte-like cells expressed metabolic enzyme FAH (as assayed by a new knock-in reporter line) and improved short-term survival in the Fah-/-Rag2-/-Il2rg-/- mouse model of liver failure. Collectively the timed signaling interventions indicated by this developmental roadmap enable accelerated production of human liver progenitors from PSCs.