Effects Of Bone Marrow-Derived Mesenchymal Stem Cells On Hypoxia And The Transforming Growth Factor Beta 1 (Tgf Beta-1) And Smads Pathway In A Mouse Model Of Cirrhosis

Background: The role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in liver fibrosis remains poorly under- stood. This study aimed to use a mouse model of carbon tetrachloride (CCL4)-induced liver fibrosis to investigate the effects of BM-MSCs during liver hypoxia and the involvement of the transforming growth factor beta 1 (TGF-beta 1) and SMADs pathway.Material/Methods: Thirty C57BL/6 mice were randomly divided into the control group (n=10), the model group (n=10), and the BM-MSC-treated model group (n=10). In the model group, liver fibrosis was induced by intraperitoneal injection of CCl4. BM-MSCs were transplanted after 12 weeks of CCl4 treatment. The serum biochemical parameters and histological changes in the liver, using histochemical stains, were investigated. The expression of collagen type I (collagen I), alpha-smooth muscle actin (alpha-SMA), TGF-beta 1, SMAD3, SMAD7, hypoxia-inducible factor 1 alpha (HIF-1 alpha), and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and quantitative real-time polymerase chain (RT-qPCR) reaction.Results: Treatment with BM-MSCs reduced the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with the model group, and reduced liver fibrosis determined histologically using hematoxylin and eosin (H&E) and Masson's trichrome staining compared with the model group. The area of liver fibrosis decreased after BM-MSCs treatment (p<0.05). Protein expression of HIF-1 alpha and VEGF were decreased after BM-MSCs treatment (p<0.05). Transplantation of BM-MSCs reduced the mRNA expression of TGF-beta 1, collagen I, alpha-SMA, and SMAD3 (p<0.05).Conclusions: BM-MSC transplantation reduced CCl4-induced murine liver fibrosis, indicating that in a hypoxic microenviron- ment, BM-MSCs may inhibit the TGF beta-1/SMADs pathway.