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      Induction of hepatic differentiation of mouse bone marrow stromal stem cells by the histone deacetylase inhibitor VPA

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          Abstract

          Bone marrow stromal stem cells (BMSSCs) may have potential to differentiate in vitro and in vivo into hepatocytes. Here, we investigated the effects of valproic acid (VPA) involved in epigenetic modification, a direct inhibitor of histone deacetylase, on hepatic differentiation of mouse BMSSCs. Following the treatment of 2.5 mM VPA for 72 hrs, the in vitro expanded, highly purified and functionally active mouse BMSSCs from bone marrow were either exposed to some well‐defined cytokines and growth factors in a sequential way (fibroblast growth factor‐4 [FGF‐4], followed by HGF, and HGF + OSM + ITS + dexamethasone, resembling the order of secretion during liver embryogenesis) or transplanted (caudal vein) in mice submitted to a protocol of chronic injury (chronic i.p. injection of CCl 4) . Additional exposure of the cells to VPA considerably improved the in vitro differentiation, as demonstrated by a more homogeneous cell population exhibited epithelial morphology, increasing expression of hepatic special genes and enhanced hepatic functions. Further more, in vivo results indicate that the pre‐treatment of VPA significantly increased the homing efficiency of BMSSCs to the site of liver injury and, additionally, for supporting hepatic differentiation as well as in vitro. We have demonstrated the usefulness of VPA in the transdifferentiation of BMSSCs into hepatocytes both in vitro and in vivo, and regulation of fibroblast growth factor receptors (FGFRs) and c‐Met gene expression through post‐translational modification of core histones might be the primary initiating event for these effects. This mode could be helpful for liver engineering and clinical therapy.

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          Author and article information

          Journal
          J Cell Mol Med
          J. Cell. Mol. Med
          10.1111/(ISSN)1582-4934
          JCMM
          Journal of Cellular and Molecular Medicine
          Blackwell Publishing Ltd (Oxford, UK )
          1582-1838
          1582-4934
          14 August 2008
          August 2009
          : 13
          : 8b ( doiID: 10.1111/jcmm.2009.13.issue-8b )
          : 2582-2592
          Affiliations
          [ 1 ]College of Life Sciences, Zhejiang University, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, P. R. China
          [ 2 ]The Molecular Medicine Center of Shaoxing People’s Hospital, The First Affiliate Hospital of Shaoxing University, Shaoxing, P. R. China
          Author notes
          [*] [* ] Correspondence to: Jian‐Zhong SHAO, College of Life Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
Tel.: +86‐571‐88206582
Fax: +86‐571‐88206582
E‐mail: shaojz@ 123456zju.edu.cn
          Article
          PMC6512375 PMC6512375 6512375 JCMM471
          10.1111/j.1582-4934.2008.00471.x
          6512375
          18705698
          e9e8e306-bffe-4789-ad33-d4c5d3995380
          © 2008 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
          History
          Page count
          Figures: 7, Tables: 2, Equations: 0, References: 29, Pages: 11
          Categories
          Tissue Regeneration
          Custom metadata
          2.0
          August 2009
          Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.3 mode:remove_FC converted:17.05.2019

          differentiation,bone marrow stromal stem cells,valproic acid,hepatocyte,epigenetic modification

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