FC 098MESENCHYMAL STEM CELL EXOSOMES AMELIORATE MICE PERITONEAL FIBROSIS INDUCED BY HUMAN PERITONITIS DIALYSIS EFFLUENT

Abstract

Abstract Background and Aims Peritoneal fibrosis is a severe complication of peritoneal dialysis, but there are few effective therapies for it. The purpose of this study was to investigate the protective effect of exosomes secreted by mouse bone marrow mesenchymal stem cells on peritoneal fibrosis and to reveal the mechanism. Method Forty-two male C57BL/6 mice were randomly divided into a normal group, a control group (2.5% glucose dialysate), a peritonitis-effluent group (The overnight 2.5% glucose dialysate of patients with peritonitis), a high glucose dialysate group (4.25% glucose concentration), a peritonitis-dialysate + exosome group, and a high glucose dialysate + exosome group. The mouse model of peritoneal fibrosis was constructed by intraperitoneal injection of human peritonitis effusion continuously for 42 days. The mice in the exosome treatment group received intraperitoneal injection of mesenchymal stem cell (MSC)-exosomes twice. The level of peritoneal structural and functional damage, inflammation, fibrosis and mesothelial cell damage of peritoneum were detected. Furthermore, the effect of MSC-exosomes was validated in vitro. Results Peritoneal transport was significantly impaired and peritoneal thickness was significantly increased in the peritonitis-effluent group and the high glucose dialysate group after 42 days. The degree of peritoneal inflammation and fibrosis in the two groups was significantly higher than the control group. The results suggested that human peritonitis dialysis effluent could be used to construct a mouse model of peritoneal fibrosis. Masson staining results showed that the fibrosis degree of peritonitis - effluent + exosome group was significantly less than the peritonitis - effluent group. Immunohistochemical analysis showed that the expression levels of mesothelial markers E-cadherin and ZO-1, neutrophil granulocytes (MPO) and macrophages (F4/80), and fibrosis markers collagen I and a-SMA in the peritonitis - effluent + exosome group were significantly lower than those in the peritonitis - effluent group. Similarly, the high glucose dialysate + exosome group mice showed significantly lower levels of peritoneal inflammation and fibrosis than the high glucose dialysate group mice. In vitro experiments showed that exosomes could down-regulate the secretion of IL-1, IL-6 and TGF- by renal tubular cells stimulated by high glucose dialysate, maintain the expression of mesenchymal cell marker (E-cadherin), and inhibit the mesenchymal marker (-SMA), suggesting that exosomes could inhibit the transdifferentiation of peritoneal mesenchymal cell-mesenchymal cells (MMT). Conclusion MSC-exosomes can alleviate peritoneal fibrosis by inhibiting peritoneal mesothelial cell-mesenchymal cell transdifferentiation.