Transplantation of bone marrow mesenchymal stromal cells attenuates liver fibrosis in mice by regulating macrophage subtypes

BACKGROUND: Liver fibrosis is a key phase that will progress to further injuries such as liver cirrhosis or carcinoma. This study aimed to investigate whether transplantation of bone marrow mesenchymal stromal cells (BM-MSCs) can attenuate liver fibrosis in mice and the underlying mechanisms based on the regulation of macrophage subtypes. METHODS: A liver fibrosis model was induced by intraperitoneal (i.p.) injection of CCl4 twice per week for 70 days, and BM-MSCs were intravenously transplanted twice on the 60th and 70th days. Immunohistology and gene expression of liver fibrosis and macrophage subtypes were analyzed. Mouse RAW264.7 cells and JS1 cells (hepatic stellate cell strain) were also used to explore the underlying mechanisms of the effects of BM-MSCs on liver fibrosis. RESULTS: After transplantation of BM-MSCs, F4/80(+)CD206(+)-activated M2 macrophages and matrix metalloproteinase 13 (MMP 13) expression were significantly increased while F4/80(+)iNOS(+)-activated M1 macrophages were inhibited in liver tissue. Gene expression of IL-10 was elevated while IL12b, IFN-γ, TNF-α, and IL-6 gene expression were decreased. ΤGF-β1 and collagen-1 secretions were reduced while caspase-3 was increased in JS1 cells treated with BM-MSC-conditioned media. BM-MSCs effectively suppressed the expression of α-SMA, Sirius red, and collagen-1 in the liver, which are positively correlated with fibrosis and induced by CCl4 injection. CONCLUSIONS: Taken together, we have provided the first demonstration that BM-MSC transplantation can promote the activation of M2 macrophages expressing MMP13 and inhibition of M1 macrophages to further inhibit hepatic stellate cells (HSCs), which play synergistic roles in attenuating liver fibrosis.