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.

Coupling Osmotic Efficacy with Biocompatibility in Peritoneal Dialysis: A Stiff Challenge

“…Similar effectiveness in the protection of PM from PD solution-induced injury and dysfunction was observed in a rat model of biologically incompatible PDS induction upon treatment with PD effluent-derived MSCs [ 120 ]. MSCs can indeed be obtained from discarded PD effluent [ 121 ], which may provide a practical unlimited source of MSCs [ 122 ]. It has to be noted that in preclinical studies the improved PF by use of SCs was associated with an improvement in peritoneal permeability function, as assessed by peritoneal UF, glucose transport, and solute permeability [ 116 ].…”

Advances in stem cell therapy for peritoneal fibrosis: from mechanisms to therapeutics

“…The secretome and soluble factors from pMSCs have shown a significant decrease in PMC death when exposed to PDS [ 36 ]…”

“…In vitro incubation with pMSC-conditioned medium (CM) prevented death in cultured human PMCs (HPMCs) and decreased proinflammatory gene expression while increasing anti-inflammatory gene expression [ 64 ]. A study by Du et al [ 36 ] published in 2021 showed that compared to UC-MSCs, pMSCs may more potently prevent PDS-induced PM injury; this effect is associated with higher resistance of pMSCs than UC-MSCs to uraemic toxins in culture and a greater reduction in PMC death by the secretome and soluble factors from pMSCs than by those from UC-MSCs in response to PDS exposure. The pMSCs represent a relatively novel type of SCs that are closely related to the peritoneum, and their relatively convenient accessibility and considerable therapeutic effects have made them promising options for anti-PF approaches.…”

“…MSCs Settlement and differentiation BM-MSCs can differentiate into MCs that participate in peritoneal repair and remodelling [34] Secretion of cytokines acts on MCs AD-MSCs release HGF and reduce PF by promoting the migration and proliferation of MCs [35] The secretome and soluble factors from pMSCs have shown a significant decrease in PMC death when exposed to PDS [36] Secretion of EVs Exosomes from BM-MSCs carry a series of miRNAs with different functions and effectively prevent PF [37] EVs from AD-MSCs can induce rat PMC proliferation and migration via stimulation of the MAPK-ERK1/2 and PI3K-AKT axes [38] Exosomal lncRNA GAS5 derived from UC-MSCs can alleviate MMT through the Wnt/β-catenin signalling pathway [39] Immunoregulation BM-MSCs secrete IL-6, IDO and exosomes that affect M2 macrophage differentiation [40][41][42] AD-MSCs attenuate PF by modulating macrophage polarization via IL-6 [43] Preconditioning of MSCs with serum-free culture conditions, IL-1β, IFN-γ, Leishmania major soluble antigens and melatonin can promote anti-inflammatory properties in peritoneal macrophages and reduce PF [40,[44][45][46] SIRT1-modified MSCs can attenuate inflammation and PF through the TGF-β/Smad3 pathway [47] USCs Secretion of EVs Exosomes from USCs alleviate tissue fibrosis via regulating miR-301b-3p/TGF-βR1 pathway [48] Immunoregulation USCs downregulate the Th1/Th17 immune responses in a PGE2-dependent manner and reduce inflammation [49] HSCs Settlement and differentiation HSCs that originate from the bone marrow have the ability to transform into MCs for repairing and remodelling the peritoneum [34] AFSCs Immunoregulation Paracrine factors produced by AFSCs cause M1-M2 macrophage polarization in a cell contactindependent way and exhibit anti-inflammatory properties [50] Among SCs from the aforementioned sources, MSCs isolated from adipose tissue and bone marrow must be obtained by invasively, and MSCs isolation from the umbilical cord may raise ethical issues, thus limiting the clinical availability of these SCs. Recently, the presence of MSCs in PDS (called pMSCs) has been described [62].…”

The path to the medical standard of treatment for patients with psoriatic arthritis — a practical guide

“…The authors of this study hope that drug programmes will be further modified to ensure greater accessibility to modern therapies in Poland for patients with rheumatic diseases. Due to the loss of patent protection of key TNFa inhibitors in rheumatology, such as adalimumab, etanercept and infliximab, bioequivalent drugs are the fastest growing group of therapies and offer the greatest hope for lower therapy costs [27]. Based on the current provisions of the Reimbursement Act, which qualify the inclusion of a bioequivalent drug in reimbursement and oblige the responsible entity to reduce the price of the bioequivalent drug by at least 25% compared to the price of the reference drug, it can be expected that the cumulative savings for the public payer from the introduction of bioequivalent drugs for monoclonal antibodies and fusion/soluble receptor proteins will be more than EUR 100 million per year in Poland.…”