Putative endothelial progenitor cells do not promote vascular repair but attenuate pericyte\u2013myofibroblast transition in UUO-induced renal fibrosis

Juan Yang,Han Zhu,Le Wang,Octavia Li-Sien Chong Lee Shin,Xiaohui Wang,Zufu Ma,Chujin Cao,Yong Ning,Rui Zeng,Meng Wang,Jie Sun,Huzi Xu,Zhi Zhao,Gang Xu,Wei Liu,Guangchang Pei,Xiaofeng He,Liu Liu,Fan Zhu ,Yi Hsiang Huang ,Ying Yao

doi:10.1186/s13287-019-1201-5

Abstract

BackgroundPutative endothelial progenitor cells (pEPCs) have been confirmed to participate in alleviation of renal fibrosis in several ischaemic diseases. However, their mechanistic effect on renal fibrosis, which is characterized by vascular regression and further rarefaction-related pathology, remains unknown.MethodsTo explore the effect and molecular mechanisms by which pEPCs act on unilateral ureteral obstruction (UUO)-induced renal fibrosis, we isolated pEPCs from murine bone marrow. In vivo, pEPCs (2 × 105 cells/day) and pEPC-MVs (microvesicles) were injected into UUO mice via the tail vein. In vitro, pEPCs were co-cultured with renal-derived pericytes. Pericyte-myofibroblast transition was evaluated using the myofibroblast marker α-smooth muscle actin (α-SMA) and pericyte marker platelet-derived growth factor receptor β (PDGFR-β).ResultsExogenous supply of bone marrow-derived pEPCs attenuated renal fibrosis by decreasing pericyte-myofibroblast transition without significant vascular repair in the UUO model. Our results indicated that pEPCs regulated pericytes and their transition into myofibroblasts via pEPC-MVs. Co-culture of pericytes with pEPCs in vitro suggested that pEPCs inhibit transforming growth factor-β (TGF-β)-induced pericyte–myofibroblast transition via a paracrine pathway.ConclusionpEPCs effectively attenuated UUO-induced renal fibrosis by inhibiting pericyte–myofibroblast transition via a paracrine pathway, without promoting vascular repair.

Highlights

Putative endothelial progenitor cells have been confirmed to participate in alleviation of renal fibrosis in several ischaemic diseases
Our results demonstrated a protective effect of Putative endothelial progenitor cells (pEPCs) on ureteral obstruction (UUO)-induced renal fibrosis; the protective effect was not due to the widely accepted mechanism of improvement of microvascular rarefaction but rather to the inhibition of pericyte detachment from endothelial cells and the pericyte–myofibroblast transition
Our results suggest that the effect of pEPCs on pericyte–myofibroblast transition was dependent on pEPC-MVs

Summary

Introduction

Putative endothelial progenitor cells (pEPCs) have been confirmed to participate in alleviation of renal fibrosis in several ischaemic diseases. Their mechanistic effect on renal fibrosis, which is characterized by vascular regression and further rarefaction-related pathology, remains unknown. Studies have proposed that stem cell-derived microvesicles (MVs) (vesicles approximately 200 nm in diameter) are complex particles formed by exocytosis of the cell membrane of pEPCs and contain a selection of proteins and RNA that can act as messengers to deliver information to distant target cells [20] Given their characteristic ability to dock to the plasma membrane or be assimilated by endocytosis, pEPC-MVs can be an effective medium for transmission of paracrine signals between cells [21, 22]

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