Peritoneal MSCs-derived exosomes suppress CCL24 synthesis through miR-320d delivery contributing to the improvement of peritoneal dialysis-associated fibrosis

Abstract

Abstract Mesothelial-to-mesenchymal transition (MMT) is a key pathological process driving peritoneal fibrosis in patients undergoing peritoneal dialysis (PD). Although Chemokine ligand 24 (CCL24) is implicated in multi-organ fibrosis, its role in MMT and PD-related fibrosis is still unknown. And the therapeutic potential of peritoneal mesenchymal stem cells (pMSCs) also remains unexplored. To elucidate the mechanistic role of CCL24 in MMT and PD-related fibrosis, and the reversal effects of human pMSCs-derived exosomes (HpMSCs-Exo) loaded with miRNAs, a series of experiments, including qRT-PCR, western blotting, ELISA, immunofluorescence, hematoxylin-eosin, and Masson’s trichrome staining, were employed. In a PD-induced peritoneal fibrosis rat model, CCL24 was significantly upregulated in peritoneal tissues, predominantly localized to macrophages. Macrophage-derived CCL24 promoted MMT via the CCR3/P38 MAPK pathway, an effect reversed by HpMSCs and their exosomes. Mechanistically, HpMSCs-Exo delivered miR-320d into macrophages. KLF7, the target gene of miR-320d, abolished the suppressive effects of miR-320d mimics and HpMSCs-Exo on STAT3 phosphorylation level and CCL24 expression in macrophages. Furthermore, HpMSCs-Exo attenuated MMT and PD-related fibrosis, with miR-320d-enriched exosomes exhibiting superior efficacy. HpMSCs-Exo deliver miR-320d into macrophages, suppressing CCL24 synthesis and secretion via the KLF7/STAT3 pathway, and thereby ameliorating MMT-driven peritoneal fibrosis. Autologous pMSCs-Exo engineered with miR-320d represent a promising therapeutic strategy for halting PD-related fibrosis progression.