Abstract
BackgroundMesenchymal stem cells (MSCs) are increasingly being applied as a therapy for liver fibrosis. Exosomes possess similar functions to their parent cells; however, they are safe and effective cell-free reagents with controllable and predictable outcomes. In this study, we investigated the therapeutic potential and underlying molecular mechanism for human bone mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) in the treatment of liver fibrosis.MethodsWe established an 8-week CCl4-induced rat liver fibrosis model, after which, we administered hBM-MSCs-Ex in vivo for 4 weeks. The resulting histopathology, liver function, and inflammatory cytokines were analyzed. In addition, we investigated the anti-fibrotic mechanism of hBM-MSCs-Ex in hepatic stellate cells (HSCs) and liver fibrosis tissue, by western blotting for the expression of Wnt/β-catenin signaling pathway-related genes.ResultsIn vivo administration of hBM-MSCs-Ex effectively alleviated liver fibrosis, including a reduction in collagen accumulation, enhanced liver functionality, inhibition of inflammation, and increased hepatocyte regeneration. Moreover, based on measurement of the collagen area, Ishak fibrosis score, MDA levels, IL-1, and IL-6, the therapeutic effect of hBM-MSCs-Ex against liver fibrosis was significantly greater than that of hBM-MSCs. In addition, we found that hBM-MSCs-Ex inhibited the expression of Wnt/β-catenin pathway components (PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, Cyclin D1), α-SMA, and Collagen I, in both HSCs and liver fibrosis tissue.ConclusionsThese results suggest that hBM-MSCs-Ex treatment could ameliorate CCl4-induced liver fibrosis via inhibition of HSC activation through the Wnt/β-catenin pathway.
Highlights
Mesenchymal stem cells (MSCs) are increasingly being applied as a therapy for liver fibrosis
HBM-MSCs-Ex alleviates CCl4-induced rats liver fibrosis The effectiveness of isolated hBM-MSCs-Ex to alleviate CCl4-induced liver fibrosis was assessed in a rat model
To further investigate the mechanism underlying the hBM-MSCs and hBM-MSCs-Ex-mediated rescue of CCl4-damaged liver, we examined the expression level of Alpha-smooth muscle actin (α-SMA), which is a key cytokine involved in the development of liver fibrosis and hepatic stellate cells (HSCs) activation (Fig. 4a, c)
Summary
Mesenchymal stem cells (MSCs) are increasingly being applied as a therapy for liver fibrosis. We investigated the therapeutic potential and underlying molecular mechanism for human bone mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) in the treatment of liver fibrosis. Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) [1]. Such chronic liver damage is a serious health problem worldwide [2]. A number of studies have evaluated the ability of mesenchymal stem cells (MSCs) to reduce liver fibrosis and improve liver function [4,5,6]. Clinical trials have demonstrated that MSC transplantation is effective in the treatment of human liver fibrosis [10]. Recent studies have suggested that a novel cell-free therapy, MSCs-secreted exosomes, may present a new therapeutic strategy due to their advantages over MSCs [12,13,14]
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