title: Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell-cell contact inhibits proliferation of hepatic stellate cells.
abstract: OBJECTIVE
  Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported in many studies to reduce liver fibrosis. Apart from the paracrine mechanism by which the antifibrotic effects of BMSCs inhibit activated hepatic stellate cells (HSCs), the effects of direct interplay and juxtacrine signaling between the two cell types are poorly understood. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated HSCs.
  
  
  METHODS
  We show here that BMSCs directly cocultured with HSCs significantly suppressed the proliferation and α-smooth muscle actin (α-SMA) expression of HSCs. Moreover, the Notch1 and Hes1 mRNA levels and the Hes1 protein level in cocultured HSCs were evidently higher than in other models. Blocking the Notch signaling pathway with Notch1 siRNA caused the increased expression of phospho-Akt and greater cell growth of cocultured HSCs. This effect was attenuated by the PI3K inhibitor LY294002.
  
  
  RESULTS
  In conclusion, our results demonstrated that BMSCs remarkably inhibited the proliferation of HSCs through a cell-cell contact mode that was partially mediated by Notch pathway activation. In addition, the PI3K/Akt pathway is involved in HSC growth inhibition by the Notch pathway.
  
  
  CONCLUSIONS
  These findings demonstrated that BMSCs directly modulate HSCs in vitro via Notch signaling cascades. Our results may provide new insights into the treatment of hepatic fibrosis with BMSCs.
authors: Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, GuangZhou 510630, PR China.
authors: Si
authors: S
authors: Chen
authors: Linan
authors: L
authors: Xu
authors: Nan
authors: N
authors: Lin
authors: Weidong
authors: W
authors: Pan
authors: Kunpeng
authors: K
authors: Hu
authors: Ruiyun
authors: R
authors: Xu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D018920:Coculture Techniques; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000473:pathology / Q000628:therapy; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000199:Actins; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; C497763:Notch1 protein, rat; C498862:Acta2 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one