Extracellular Vesicle-Packaged ILK From Mesothelial Cells Promotes Fibroblast Activation in Peritoneal Fibrosis

Authors

Qiang Huang
Yuxiang Sun
Long Peng
Juan Sun
Zixin Sha
Hongchun Lin
Yongjie Li
Canming Li
Huiqun Li
Hongli Shang
Yanxu Chen
Xianrui Dou
Zhaoyong Hu
Zengchun Ye
Hui Peng

Publication Date

7-1-2023

Journal

Journal of Extracellular Vesicles

DOI

10.1002/jev2.12334

PMID

37357686

PMCID

PMC10291285

PubMedCentral® Posted Date

6-26-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Peritoneal Fibrosis, Extracellular Vesicles, Peritoneal Dialysis, Fibroblasts, cell‐cell communication, extracellular vesicles, ILK, peritoneal dialysis, peritoneal fibrosis, peritoneum

Abstract

Progressive peritoneal fibrosis and the loss of peritoneal function often emerged in patients undergoing long-term peritoneal dialysis (PD), resulting in PD therapy failure. Varieties of cell-cell communications among peritoneal cells play a significant role in peritoneal fibrogenesis. Extracellular vesicles (EVs) have been confirmed to involve in intercellular communication by transmitting proteins, nucleic acids or lipids. However, their roles and functional mechanisms in peritoneal fibrosis remain to be determined. 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 integrin-linked kinase (ILK), which was delivered to fibroblast and activated them via p38 MAPK signalling pathway. Clinically, the expression of ILK was up-regulated in fibrotic peritoneum of patients undergoing long-term PD. The percentage of ILK positive EVs in PD effluent correlated with peritoneal dysfunction and the degree of peritoneal damage. 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.

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