Abstract
AimsBone marrow-derived mesenchymal stem cells (BMSCs) can reduce liver fibrosis. Apart from the paracrine mechanism by which the antifibrotic effects of BMSCs inhibit activated hepatic stellate cells (HSCs), the effects of direct interplay and juxtacrine signaling between the two cell types are poorly understood. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated HSCs.MethodsWe used BMSCs directly and indirectly co-culture system with HSCs to evaluate the anti-fibrosis effect of BMSCs. Cell proliferation and activation were examined in the presence of BMSCs and HGF. c-met was knockdown in HSCs to evaluate the effect of HGF secreted by BMSCs. The TLR4 and Myeloid differentiation primary response gene 88(MyD88) mRNA levels and the NF-kB pathway activation were determined by real-time PCR and western blotting analyses. The effect of BMSCs on HSCs activation was investigated in vitro in either MyD88 silencing or overexpression in HSCs. Liver fibrosis in rats fed CCl4 with and without BMSCs supplementation was compared. Histopathological examinations and serum biochemical tests were compared between the two groups.ResultsBMSCs remarkably inhibited the proliferation and activation of HSCs by interfering with LPS-TLR4 pathway through a cell–cell contact mode that was partially mediated by HGF secretion. The NF-kB pathway is involved in HSCs activation inhibition by BMSCs. MyD88 over expression reduced the BMSC inhibition of NF-kB luciferase activation. BMSCs protected liver fibrosis in vivo.ConclusionBMSCs modulate HSCs in vitro via TLR4/MyD88/NF-kB signaling pathway through cell–cell contact and secreting HGF. BMSCs have therapeutic effects on cirrhosis rats. Our results provide new insights into the treatment of hepatic fibrosis with BMSCs.
Highlights
Liver fibrosis is the excessive deposition of extracellular matrix and scar formation surrounding damaged liver and this can be effectively reversed [1,2]
extracellular matrix (ECM) production is the primary reason for the excessive fibrosis formation, which eventually leads to cirrhosis
The bone marrow cells after the 3rd passage were of high purity, and expressed CD44+, CD90+, CD342 and CD452, which are markers for Bone marrow-derived mesenchymal stem cells (BMSCs)
Summary
Liver fibrosis is the excessive deposition of extracellular matrix and scar formation surrounding damaged liver and this can be effectively reversed [1,2]. Acquired fibrosis may result from the action of a number of pathogenic factors, toxic exposures, chronic viral hepatitis or the presence of non-alcoholic fatty liver disease. These etiological factors may work separately or in combination with each other to produce cumulative effects [3]. TLR4 signals through adaptor proteins, including MyD88, to activate down-stream effectors that include NF-kB, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K). These pathways regulate the expression of pro-inflammatory cytokines and genes that control cell survival and apoptosis
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