Adipose-Derived Mesenchymal Stem Cells Modulate Fibrosis and Inflammation in the Peritoneal Fibrosis Model Developed in Uremic Rats

Abstract

Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting the peritoneal membrane (PM) function. Adipose tissue-derived mesenchymal stem cells (ASC) display immunomodulatory effects and may represent a strategy to block PF. The aim of this study was to analyze the effect of ASC in an experimental PF model developed in uremic rats. To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and chronic kidney disease (CKD), was developed in Wistar rats. Rats were fed with a 0.75% adenine-containing diet, for 30 days, to induce CKD with uremia. PF was induced with intraperitoneal injections of chlorhexidine gluconate (CG) from day 15 to 30. 1×106 ASC were intravenously injected at days 15 and 21. Rats were divided into 5 groups: control, normal rats; CKD, rats receiving adenine diet; PF, rats receiving CG; CKD+PF, CKD rats with PF; CKD+PF+ASC, uremic rats with PF treated with ASC. PF was assessed by Masson trichrome staining. Inflammation- and fibrosis-associated factors were assessed by immunohistochemistry, multiplex analysis, and qPCR. When compared with the control and CKD groups, GC administration induced a striking increase in PM thickness and inflammation in the PF and CKD+PF groups. The development of PF was blocked by ASC treatment. Further, the upregulation of profibrotic factors (TGF-β, fibronectin, and collagen) and the increased myofibroblast expression observed in the CKD+PF group were significantly ameliorated by ASC. Beyond the antifibrotic effect, ASC showed an anti-inflammatory effect avoiding leucocyte infiltration and the overexpression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the PM induced by GC. ASC were effective in preventing the development of PF in the experimental model of CKD+PF, probably due to their immunomodulatory properties. These results suggest that ASC may represent a potential strategy for treating long-term PD-associated fibrosis.

Mesenchymal Stromal Cells Suppress Hepatic Fibrosis Via Modulating the Expression of Fibronectin and Integrin and Inhibiting DNA Fragmentation in Rats

“…According to this system, a significant improvement of hepatic fibrosis was shown in the MSCs group compared to diseased and silymarin groups. Our findings were confirmed by previous studies which also indicate that MSCs inhibit the production of profibrotic factors as fibronectin and integrin which was observed in our study [36,37].…”

Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis

“…chlorhexidine gluconate (CG) injections ( Bhattacharyya et al., 2018 ). Since this inducible model reproduces many fundamental processes underlying the pathogenesis of SSc, including inflammation, myofibroblast accumulation, and extracellular matrix accumulation, it is used widely to investigate pathogenic mechanisms of fibrosis ( Costalonga et al., 2020 ; Kitamura et al., 2015 ). Mice lacking CD38 suffered less weight loss during the course of CG treatment and showed significantly attenuated peritoneal membrane thickening and collagen deposition ( Figures S6 A and S6B).…”

Blocking core fucosylation of epidermal growth factor (EGF) receptor prevents peritoneal fibrosis progression

“…Peritoneal dialysis (PD), a type of home dialysis therapy for end-stage renal disease, has been widely used across the world because of its convenience and flexibility [ 1 ], especially in the current COVID-19 pandemic [ 2 ]. However, long-term PD treatment will result in peritoneal fibrosis, a frequent complication due to exposure to glucose peritoneal dialysate [ 3 , 4 ]. Peritoneal fibrosis may affect the function of the peritoneal membrane and ultimately lead to ultrafiltration failure and discontinuation of PD [ 5 , 6 ].…”