TY - JOUR T1 - Accelerated human liver progenitor generation from pluripotent stem cells by inhibiting formation of unwanted lineages JF - bioRxiv DO - 10.1101/174698 SP - 174698 AU - Lay Teng Ang AU - Antson Kiat Yee Tan AU - Matias Ilmari Autio AU - Joanne Su-Hua Goh AU - Siew Hua Choo AU - Kian Leong Lee AU - Jianmin Tan AU - Bangfen Pan AU - Jane Jia Hui Lee AU - Isabelle Kai Xin Yeo AU - Chloe Jin Yee Wong AU - Jen Jen Lum AU - Chet Hong Loh AU - Ying Yan Lim AU - Jueween Ling Li Oh AU - Cheryl Pei Lynn Chia AU - Angela Chen AU - Qing Feng Chen AU - Irving L. Weissman AU - Kyle M. Loh AU - Bing Lim Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/08/10/174698.abstract N2 - 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. ER -