title: Generation of Self-Renewing Hepatoblasts From Human Embryonic Stem Cells by Chemical Approaches.
abstract: Somatic stem cells play crucial roles in organogenesis and tissue homeostasis and regeneration and may ultimately prove useful for cell therapy for a variety of degenerative diseases and injuries; however, isolation and expansion of most types of somatic stem cells from tissues are technically challenging. Human pluripotent stem cells are a renewable source for any adult cell types, including somatic stem cells. Generation of somatic stem cells from human pluripotent stem cells is a promising strategy to get these therapeutically valuable cells. Previously, we developed a chemically defined condition for mouse hepatoblast self-renewal through a reiterative screening strategy. In the present study, we efficiently generated hepatoblasts from human embryonic stem cells by a stepwise induction strategy. Importantly, these human embryonic stem cell-derived hepatoblasts can be captured and stably maintained using conditions previously established for mouse hepatoblast self-renewal, which includes basal media supplemented with insulin, transferrin, sodium selenite, epidermal growth factor, glycogen synthase kinase 3 inhibitor, transforming growth factor β receptor inhibitor, lysophosphatidic acid, and sphingosine 1-phosphate. The cells can stably retain hepatoblast phenotypes during prolonged culture and can differentiate into mature hepatocytes through in vitro provision of hepatocyte lineage developmental cues. After being embedded into three-dimensional Matrigel, these cells efficiently formed bile duct-like structures resembling native bile duct tissues. These human embryonic stem cell-derived hepatoblasts would be useful as a renewable source for cell therapy of liver diseases.
  
  
  CONCLUSIONS
  Somatic stem cells have been proposed as promising candidates for cell-based therapy; however, isolation of somatic stem cells from adult tissues is usually invasive and technically challenging. In the present study, hepatoblasts from human embryonic stem cells were efficiently generated. These human hepatoblasts were then stably captured and maintained by a growth factor and small molecule cocktail, which included epidermal growth factor, glycogen synthase kinase 3 inhibitor, transforming growth factor β receptor inhibitor, lysophosphatidic acid, and sphingosine 1-phosphate. These human embryonic stem cell-derived hepatoblasts would be useful as a renewable source for cell therapy of liver diseases.
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Muzi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Pingxin
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Junnan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Linjie
authors.initials: L
authors.lastname: Lv
authors.affiliation: Stem Cell and Regenerative Medicine Center, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, People's Republic of China liwenlin@smmu.edu.cn jincx@tongji.edu.cn weiwg@sari.ac.cn.
authors.forename: Wanguo
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Regenerative Medicine, College of Medicine, Tongji University, Shanghai, People's Republic of China liwenlin@smmu.edu.cn jincx@tongji.edu.cn weiwg@sari.ac.cn.
authors.forename: Caixia
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China liwenlin@smmu.edu.cn jincx@tongji.edu.cn weiwg@sari.ac.cn.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D003470:Culture Media / Q000737:chemistry* / Q000494:pharmacology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice
chemical_list: D003470:Culture Media
keywords: Chemical approaches; Differentiation; Hepatoblasts; Human embryonic stem cells