Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms.

Aim: During fibrosis, hepatic stellate cells (HSCs) undergo a complex activation process characterized by increased proliferation and extracellular matrix deposition. Previous studies have suggested that mesenchymal stem cells (MSCs) may ameliorate fibrogenesis and represent a promising strategy for cell therapy. However, the underlying mechanisms are not fully understood. Methods: Hepatic stellate cells were treated with or without MSCs. Then cell proliferation and cell cycle were analyzed. Production of soluble factors by MSCs and its relation with cell proliferation suppression was evaluated by transwell co-culture and RNA interference. Effects of MSCs on the gene expression of collagen were also evaluated. Results: MSCs induced G(0)/G(1) arrest of HSCs growth partly through secreting soluble factors TGF-beta 3 and HGF, which resulted in up-regulation of p21Cip1 and p27Kip1 expression and down-regulation of cyclinD1. MSCs inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and reduced gene expression of collagen type I and III. MSCs did not reverse the proliferation and collagen type I gene expression of HSCs provoked by PDGF. Conclusions: The growth inhibition of HSCs induced by MSCs through an arrest in the G(0)/G(1) phase of the cell cycle is partially mediated by secretion of TGF-beta 3 and HGF. MSCs inhibit HSCs activation through decreasing phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. These results further support MSCs may be used as a novel therapy for treating fibrotic diseases in human.