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Comparison of mesenchymal stromal cells from peritoneal dialysis effluent with those from umbilical cords: characteristics and therapeutic effects on chronic peritoneal dialysis in uremic rats.

ABSTRACT:

Background

A long-term of peritoneal dialysis (PD) using a hypertonic PD solution (PDS) leads to patient's peritoneal membrane (PM) injury, resulting in ultrafiltration failure (UFF) and PD drop-out. Our previous study shows that PD effluent-derived mesenchymal stromal cells (pMSCs) prevent the PM injury in normal rats after repeated exposure of the peritoneal cavity to a PDS. This study was designed to compare the cytoprotection between pMSCs and umbilical cord-derived MSCs (UC-MSCs) in the treatment of both PM and kidney injury in uremic rats with chronic PD.

Methods

5/6 nephrectomized (5/6Nx) Sprague Dawley rats were intraperitoneally (IP) injected Dianeal (4.25% dextrose, 10 mL/rat/day) and were treated with pMSCs or umbilical cord (UC)-MSCs (approximately 2 × 10⁶/rat/week, IP). Ultrafiltration was determined by IP injection of 30 mL of Dianeal (4.25% dextrose) with 1.5-h dewell time, and kidney failure by serum creatinine (SCr) and blood urea nitrogen (BUN). The structure of the PM and kidneys was assessed using histology. Gene expression was examined using quantitative reverse transcription PCR, and protein levels using flow cytometric and Western blot analyses.

Results

We showed a slight difference in the morphology between pMSCs and UC-MSCs in plastic dishes, and significantly higher expression levels of stemness-related genes (NANOG, OCT4, SOX2, CCNA2, RAD21, and EXO1) and MSCs surface markers (CD29, CD44, CD90 and CD105) in UC-MSCs than those in pMSCs, but no difference in the differentiation to chondrocytes, osteocytes or adipocytes. pMSC treatment was more effective than UC-MSCs in the protection of the MP and remnant kidneys in 5/6Nx rats from PDS-induced injury, which was associated with higher resistance of pMSCs than UC-MSCs to uremic toxins in culture, and more reduction of peritoneal mesothelial cell death by the secretome from pMSCs than from UC-MSCs in response to PDS exposure. The secretome from both pMSCs and UC-MSCs similarly inactivated NOS2 in activated THP1 cells.

Conclusions

As compared to UC-MSCs, pMSCs may more potently prevent PDS-induced PM and remnant kidney injury in this uremic rat model of chronic PD, suggesting that autotransplantation of ex vivo-expanded pMSCs may become a promising therapy for UFF and deterioration of remnant kidney function in PD patients.

SUBMITTER: Du Y

PROVIDER: S-EPMC8278755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.