title: Transcription factor-mediated reprograming of fibroblasts to hepatocyte-like cells.
abstract: Direct conversion by overexpression of defined transcription factors (TFs) is a promising new method that can generate desired cell types from abundant, accessible cells. While previous studies have reported hepatic generation from fibroblasts, tremendous interest exists in the understanding of hepatic reprograming and its applicability in regenerative medicine. Here, we show that overexpression of Yamanaka factors can induce reprograming of mouse fibroblasts into cells that closely resemble hepatocytes in vitro in the presence of an optimized hepatic growth medium. By screening the effects of 20 candidate transcription factors, we identified a combination of three TFs (Hnf4a, Cebpa, and Nr1i2) that can convert fibroblasts into a hepatic fate. These factors in conjunction with Yamanaka factors increase the efficiency of hepatic reprograming. The induced hepatocyte-like (iHep) cells have multiple hepatocyte-specific characteristics; express hepatocyte-specific markers, glycogen storage, albumin secretion, urea production, as well as low-density lipoprotein and indocyanin green uptake. Production of iHep cells by these novel approaches may bring new insights into the molecular nature of hepatocyte differentiation and future cell-based therapeutics for liver diseases.
authors.affiliation: Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran.
authors.forename: Behshad
authors.initials: B
authors.lastname: Pournasr
authors.affiliation: Animal Core Facility, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Tehran, Iran.
authors.forename: Mohammad Hassan
authors.initials: MH
authors.lastname: Asghari-Vostikolaee
authors.affiliation: Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran. Electronic address: Baharvand@RoyanInstitute.org.
authors.forename: Hossein
authors.initials: H
authors.lastname: Baharvand
mesh_terms: D000818:Animals; D048430:Cell Shape; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming; D003470:Culture Media; D005347:Fibroblasts / Q000502:physiology*; D006003:Glycogen / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D003470:Culture Media; D014157:Transcription Factors; D006003:Glycogen
keywords: Direct conversion; Hepatic-specific transcription factors; Hepatocyte-like cells; Yamanaka factors