Abstract
BackgroundLiver 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.MethodsA 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.ResultsAfter 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.ConclusionsTaken 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.
Highlights
Liver fibrosis is a key phase that will progress to further injuries such as liver cirrhosis or carcinoma
The animals were randomized into three groups as follows: (1) normal control group (n = 10)—treated with i.p. injection of saline twice per week for 70 days; (2) fibrosis group (n = 10)—treated with i.p. injection of Carbon tetrachloride (CCl4) twice per week for 70 days; and (3) fibrosis+Mesenchymal stromal cells (MSCs) group (n = 12)—treated with CCl4 twice per week for 70 days and treated with an injection of bone marrow mesenchymal stromal cells (BM-MSCs) via the tail vein at a dose of 5 × 105 on the 60th day and 70th day
In conclusion, irritative factors such as CCl4 injection stimulate the proliferation of M1 macrophages, which further trigger Hepatic stellate cell (HSC) activation into α-Smooth muscle actin (SMA)-positive myofibroblasts to accelerate the development of liver fibrosis by expressing Tumor necrosis factor (TNF)-α, IFN-γ, and IL-6
Summary
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. Liver fibrosis is a key period in the development of almost any liver disease that involves gradual destruction and will progress to liver cirrhosis or Mesenchymal stromal cells (MSCs) are currently attracting great attention from researchers because they are associated with fewer ethical concerns than embryonic stem cells; on the other hand, they are poor stimulators of the allogeneic T cell response in vitro and do not trigger a strong host inflammatory response in vivo [5, 6] because they only express low levels of type I HLA and do not express type II HLA and the costimulatory molecules CD40, CD80, and CD86 [5]. Due to the abundance of innate immune cells in the liver, the polarization of macrophages after BM-MSC transplantation attracted our interest
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