Mesothelial Extracellular Vesicles Promote Fibroblast Activation via Delivering of Integrin-Linked Kinase in Peritoneal Fibrosis
- Home Dialysis - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
- 802 Dialysis: Home Dialysis and Peritoneal Dialysis
- Huang, Qiang, The Third Affiliated Hospital of Sun Yet-sun University Department of Nephrology, Guangzhou, Guangdong, China
- Sun, Yuxiang, The Third Affiliated Hospital of Sun Yet-sun University Department of Nephrology, Guangzhou, Guangdong, China
- Peng, Hui, The Third Affiliated Hospital of Sun Yet-sun University Department of Nephrology, Guangzhou, Guangdong, China
Varieties of cell-cell communications among peritoneal cells play a significant role in peritoneal fibrogenesis induced by peritoneal dialysis (PD). Extracellular vesicles (EVs) have been confirmed to involve in intercellular communication by transmitting various molecules. However, their roles and functional mechanisms in peritoneal fibrosis remain to be determined.
We performed combined analysis of PD effluent-derived EV proteomics and peritoneal single-cell RNA sequencing to determine the cell source of PD effluent-derived EVs. We blocked mesothelial EVs secretion via GW4869 or shRab27a, and injected mesothelial EVs into mice treated with PD fluid. We detected the percentage of ILK+ EVs in PD effluent by flow cytometry.
Using integrative analysis of EV proteomics and single-cell RNA sequencing, we characterized the EVs isolated from PD patient’s effluent and revealed that mesothelial cells are the main source of EVs in PD effluent. We demonstrated that transforming growth factor-β1 (TGF-β1) can substitute for PD fluid to stimulate mesothelial cells releasing EVs, which in turn promoted fibroblast activation and peritoneal fibrogenesis. Blockade of EVs secretion by GW4869 or Rab27a knockdown markedly suppressed PD-induced fibroblast activation and peritoneal fibrosis. Mechanistically, injured mesothelial cells produced EVs containing high level of ILK, which was delivered to fibroblast and activated them. Clinically, the percentage of ILK positive EVs in PD effluent correlated with peritoneal dysfunction.
Our study highlights that peritoneal EVs mediate communications between mesothelial cells and fibroblasts to initiate peritoneal fibrogenesis. Targeting EVs or ILK could provide a novel therapeutic strategy to combat peritoneal fibrosis.