title: Efficient programming of human mesenchymal stem cell-derived hepatocytes by epigenetic regulations.
abstract: OBJECTIVE
  In view of its unique properties of detoxification and involvement of metabolic and biochemical functions, in vitro hepatocyte culture serves as a valuable material for drug screening and mechanistic analysis for pathology of liver diseases. The restriction of rapid de-differentiation and inaccessibility of human hepatocytes from routine clinical procedure, however, limits its use.
  
  
  METHODS
  To address this issue, the effort to direct human mesenchymal stem cells (hMSCs) into hepatocytes using a modified protocol was proposed. With the additional treatment of histone deacetylase inhibitor (HDACi) and DNA methyltransferase inhibitor (DNMTi), in vitro hMSC-derived hepatocytes were cultivated and their hepatic characteristics were examined.
  
  
  RESULTS
  By using a modified protocol, it was shown that Trichostatin A and 5-aza-2-deoxycitidine protected differentiating cells from death and could sufficiently trigger a wide range of liver-specific markers as well as liver functions including albumin production, glycogen storage, and urea cycle in hMSC-derived hepatocytes. The increased mRNA expression for hepatitis C virus (HCV) entry including CD81, Occludin, LDL receptor, and scavenger receptor class B type I in hMSC-derived hepatocytes was also detected, implying its potential to be utilized as an in vitro model to analyze dynamic HCV infection.
  
  
  CONCLUSIONS
  The present study successfully established a protocol to direct hMSCs into hepatocyte-like cells suggesting the beneficial impact to apply HDACi and DNMTi as potent modulators for hMSCs to liver differentiation.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.|Medical School, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Tsai
authors.affiliation: Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Po-Hung
authors.initials: PH
authors.lastname: Yeh
authors.affiliation: Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.|Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Yun
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan.
authors.forename: Chin-Tsung
authors.initials: CT
authors.lastname: Ting
authors.affiliation: Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.
authors.forename: Yen-Hui
authors.initials: YH
authors.lastname: Chiu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Mi-Hua
authors.initials: MH
authors.lastname: Tao
authors.affiliation: Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.|Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.|Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Li
authors.affiliation: Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Integrative Stem Cell Center, Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D022781:Hepatocytes; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: 5-Aza-2-deoxycitidine; differentiation; hepatocytes; hepatocytestrichostatin A; human mesenchymal stem cells