Accelerated human liver progenitor generation from pluripotent stem cells by inhibiting formation of unwanted lineages
Year: 2017
Type: preprint
Abstract: 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.
DOI: 10.1101/174698
Authors: Lay Teng Ang, Antson Kiat Yee Tan, Matias Ilmari Autio, Joanne Su-Hua Goh, Siew Hua Choo, Kian Leong Lee, Jianmin Tan, Bangfen Pan, Jane Jia Hui Lee, Isabelle Kai Xin Yeo, Chloe Jin Yee Wong, Jen Jen Lum, Chet Hong Loh, Ying Yan Lim, Jueween Ling Li Oh, Cheryl Pei Lynn Chia, Angela Chen, Qing Feng Chen, Irving L. Weissman, Kyle M. Loh, Bing Lim
Institutions: Agency for Science, Technology and Research, Genome Institute of Singapore, National University Health System, National University of Singapore, Duke-NUS Medical School, Temasek Polytechnic, Stanford Medicine, Institute for Stem Cell Biology and Regenerative Medicine, University of California, Berkeley, Stanford University, Institute of Molecular and Cell Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2744477384