Induction of hepatic differentiation of mouse bone marrow  stromal stem cells by the histone deacetylase inhibitor VPA.
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 CCl4). 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.
Chen
Ye
Y
College of Life Sciences, Zhejiang University, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, P. R. China.
Pan
Ruo-Lang
RL
College of Life Sciences, Zhejiang University, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, P. R. China.
Zhang
Xiao-Lei
XL
College of Life Sciences, Zhejiang University, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, P. R. China.
Shao
Jian-Zhong
JZ
College of Life Sciences, Zhejiang University, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, P. R. China.
Xiang
Li-Xin
LX
College of Life Sciences, Zhejiang University, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, P. R. China.
Dong
Xue-Jun
XJ
The Molecular Medicine Center of Shaoxing People's Hospital, The First Affiliate Hospital of Shaoxing University, Shaoxing, P. R. China.
Zhang
Guo-Rong
GR
The Molecular Medicine Center of Shaoxing People's Hospital, The First Affiliate Hospital of Shaoxing University, Shaoxing, P. R. China.
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000494:pharmacology*
D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid