Micro‐vesicles derived from human Wharton's Jelly mesenchymal stromal cells mitigate renal ischemia‐reperfusion injury in rats after cardiac death renal transplantation

Abstract

The purpose of the present study was to investigate the possible therapeutic effects of the human Wharton-Jelly mesenchymal stromal cells derived micro-vesicles (hWJMSCs-MVs) on renal ischemia-reperfusion injury (IRI) after cardiac death (CD) renal transplantation in rats. MVs were injected intravenously in rats immediately after renal transplantation. The animals were sacrificed at 24 h, 48 h, 1 and 2 weeks post-transplantation. ELISA was used to determine the von Willebrand Factor (vWF), tumor necrosis factor (TNF)-α, and interleukin (IL)-10 levels in the serum. Tubular cell proliferation and apoptosis were identified by Ki67 immunostaining and TUNEL assay. Renal fibrosis was assessed by Masson's tri-chrome straining and alpha-smooth muscle actin (α-SMA) staining. The infiltration of inflammatory cells was detected by CD68 staining. The transforming growth factor (TGF)-β, hepatocyte growth factor (HGF), and α-SMA expression in the kidney was measured by Western blot. After renal transplantation, the rats treated with hWJMSCs-MVs improved survival rate and renal function. Moreover, MVs mitigated renal cell apoptosis, enhanced proliferation, and alleviated inflammation at the first 48 h. In the late period, abrogation of renal fibrosis was observed in the MVs group. MVs also could decrease the number of CD68 macrophages in the kidney. Furthermore, MVs decreased the protein expression levels of α-SMA and TGF-β1 and increased the protein expression level of HGF at any point (24 h, 48 h, 1 or 2 weeks). The administration of MVs immediately after renal transplantation could ameliorate IRI in both the acute and chronic stage.

Potential Applications of Extracellular Vesicles in Solid Organ Transplantation

“…Whereas all the studies mentioned above evaluated classical ischemic damage in models of renal artery clamping, Wu and co-workers tested for the first time the effect of EVs in a rat model of IRI after DCD renal transplantation [67]. The authors confirmed that Wharton's jelly MSC-EVs, intravenously injected after renal transplantation, mitigated renal damage, improving survival and function.…”

“…The authors confirmed that Wharton's jelly MSC-EVs, intravenously injected after renal transplantation, mitigated renal damage, improving survival and function. In particular, MSC-EVs were shown to reduce cell apoptosis and inflammation, to stimulate HGF production, and subsequently to alleviate fibrosis [67].…”

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

“…Murine studies in which MSC-EVs were employed as a therapeutic tool for IRI are summarized in Table 4 (166,177,(182)(183)(184)(185)(186)(187)(188)(189)(190)(191)(192)(193)(194). In all of them, administration of MSC-EVs improved renal function and/or decreased tubular injury through multiple mechanisms (164).…”

“…Increased proliferation of renal tubule epithelial cells (190) Rat adipose tissue Inhibition of oxidative stress, apoptosis, renal fibrosis (191) Human umbilical cord Increased proliferation and fibrosis (releasing from G2/M cell cycle arrest) (192) Human bone marrow Inhibition of apoptosis (downregulation of Sema3A expression and activation of AKT/ERK pathways through miR-199a-3p); inhibition of NK (193) Human umbilical cord Inhibition of apoptosis, increased proliferation of renal tubule epithelial cells; reduced CD68+macrophages infiltration; reduced fibrosis (decreased expression of aSMA and TGFβ; increased expression of HGF) (194) Human BM Suppression of endoplasmic reticulum stress (miR-199a-5p)…”

Current Perspectives on Role of MSC in Renal Pathophysiology

“…Several preclinical studies have shown that the administration of exogenous MSCs prevents kidney damage and promotes kidney recovery through a complex series of mechanisms, particularly via the regulation of the immune system and release of paracrine factors and MVs ( Wu et al, 2018 ).…”