Pericyte-myofibroblast Transition: A novel mechanism in peritoneal fibrosis and the effect of Asiaticoside
Introduction: Peritoneal fibrosis (PF), a major complication of long-term peritoneal dialysis (PD), is characterized by excessive extracellular matrix (ECM) deposition mediated by activated myofibroblasts (MyoFs). While mesenchymal transition of mesothelial cells has been widely studied, the cellular origins of MyoFs remain incompletely defined. Recent evidence suggests pericytes-mural cells surrounding microvessels-may contribute to fibrosis in other organs, but their role in PF pathogenesis is undefined.Objective: This study aimed to clarify pericyte-myofibroblast transition (PMT) as a novel mechanism in PF, investigate the role of platelet-derived growth factor receptor-beta (PDGFR beta) signaling in orchestrating PMT, and evaluate the therapeutic potential of natural triterpenoid asiaticoside (ASI) against PDGFR beta-driven fibrosis.Methods and Results: Through single-cell RNA sequencing of chlorhexidine gluconate (CG)-induced PF mice, we identified two MyoFs subpopulations (Fibro5 and Fibro7) exhibiting pericyte lineage signatures, with trajectory inference confirming their differentiation from pericytes during fibrosis. Pharmacological and genetic approaches demonstrated that PDGFR beta signaling orchestrates PMT, as evidenced by upregulated a-smooth muscle actin (a-SMA), PDGFR beta, and ECM markers (collagen I, fibronectin) in PF mice and TGF-beta1/PDGF-BB-stimulated mouse peritoneal microvascular pericytes. Remarkably, ASI attenuated PF by suppressing PDGFR beta expression by 50% and disrupting pericyte-endothelial interactions, which led to a marked reduction in peritoneal thickness (by ~69%) and collagen deposition (by ~78%). Proteomics analysis provided a perspective for analyzing the downstream mechanisms. Mechanistically, ASI mimicked PDGFR beta knockout effects, reducing MyoFs accumulation and abrogating PDGFR beta-induced Erk and Pi3k/Akt activation.Conclusion: Our findings repositioned pericytes as pivotal contributors to PF and proposed ASI as a therapeutic agent against PDGFR beta-driven PMT, which provided a new perspective for antifibrotic strategies.