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Reprogramming Fibroblasts into Bipotential Hepatic Stem Cells by Defined Factors
Bing Yu1, 2, 11, Zhi-Ying He1, 2, 11, Pu You1, 2, 10, Qing-Wang Han1, 2, Dao Xiang1, 2, Fei Chen1, 2, Min-Jun Wang1, 2, Chang-Cheng Liu1, 2, Xi-Wen Lin3, Uyunbilig Borjigin4, Xiao-Yuan Zi1, 2, Jian-Xiu Li1, 2, Hai-Ying Zhu1, 2, Wen-Lin Li1, 2, Chun-Sheng Han3, Kirk J. Wangensteen5, Yufang Shi6, 7, Li-Jian Hui8, Xin Wang4, 8, 9, , , Yi-Ping Hu1, 2
Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem or progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage conversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering.
