title: Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors.
abstract: 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.
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: He
authors.forename: Pu
authors.initials: P
authors.lastname: You
authors.forename: Qing-Wang
authors.initials: QW
authors.lastname: Han
authors.forename: Dao
authors.initials: D
authors.lastname: Xiang
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Min-Jun
authors.initials: MJ
authors.lastname: Wang
authors.forename: Chang-Cheng
authors.initials: CC
authors.lastname: Liu
authors.forename: Xi-Wen
authors.initials: XW
authors.lastname: Lin
authors.forename: Uyunbilig
authors.initials: U
authors.lastname: Borjigin
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Zi
authors.forename: Jian-Xiu
authors.initials: JX
authors.lastname: Li
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zhu
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Li
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Han
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Wangensteen
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
authors.forename: Li-Jian
authors.initials: LJ
authors.lastname: Hui
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Hu
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000196:embryology; D002460:Cell Line; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy*; D005347:Fibroblasts / Q000502:physiology*; D048091:Guided Tissue Regeneration; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology*; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000293:injuries; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D038081:Organogenesis; D011725:Pyridines / Q000008:administration & dosage; D033581:Stem Cell Transplantation
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C496506:Foxa3 protein, mouse; C496496:Hnf1b protein, mouse; D011725:Pyridines; D051543:Hepatocyte Nuclear Factor 3-gamma; D051539:Hepatocyte Nuclear Factor 1-beta; D006867:Hydrolases; C020156:fumarylacetoacetase