title: Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction.
abstract: Hepatocyte-like cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are expected to be a useful source of cells drug discovery. Although we recently reported that hepatic commitment is promoted by transduction of SOX17 and HEX into human ESC- and iPSC-derived cells, these hepatocyte-like cells were not sufficiently mature for drug screening. To promote hepatic maturation, we utilized transduction of the hepatocyte nuclear factor 4α (HNF4α) gene, which is known as a master regulator of liver-specific gene expression. Adenovirus vector-mediated overexpression of HNF4α in hepatoblasts induced by SOX17 and HEX transduction led to upregulation of epithelial and mature hepatic markers such as cytochrome P450 (CYP) enzymes, and promoted hepatic maturation by activating the mesenchymal-to-epithelial transition (MET). Thus HNF4α might play an important role in the hepatic differentiation from human ESC-derived hepatoblasts by activating the MET. Furthermore, the hepatocyte like-cells could catalyze the toxication of several compounds. Our method would be a valuable tool for the efficient generation of functional hepatocytes derived from human ESCs and iPSCs, and the hepatocyte-like cells could be used for predicting drug toxicity.
authors: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors: Kazuo
authors: K
authors: Takayama
authors: Mitsuru
authors: M
authors: Inamura
authors: Kenji
authors: K
authors: Kawabata
authors: Kazufumi
authors: K
authors: Katayama
authors: Maiko
authors: M
authors: Higuchi
authors: Katsuhisa
authors: K
authors: Tashiro
authors: Aki
authors: A
authors: Nonaka
authors: Fuminori
authors: F
authors: Sakurai
authors: Takao
authors: T
authors: Hayakawa
authors: Miho Kusuda
authors: MK
authors: Furue
authors: Hiroyuki
authors: H
authors: Mizuguchi
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D018014:Gene Transfer Techniques; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D019859:Proto-Oncogene Proteins c-met