Impact of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Rat Model of Kidney Rejection

Abstract

Background: Mesenchymal stromal cells (MSCs) from different sources possess great therapeutic potential due to their immunomodulatory properties associated with allograft tolerance. However, a crucial role in this activity resides in extracellular vesicles (EVs) and signaling molecules secreted by cells. This study aimed to evaluate the immunomodulatory properties of donor and recipient MSCs isolated from adipose tissue (AD) or bone marrow (BM) and their EVs on kidney outcome in a rat kidney transplant model. Methods: The heterotopic-kidney-transplant Fisher-to-Lewis rat model (F-L) was performed to study mixed cellular and humoral rejection. After kidney transplantation, Lewis recipients were assigned to 10 groups; two control groups; four groups received autologous MSCs (either AD-or BM-MSC) or EVs (derived from both cell types); and four groups received donor-derived MSCs or EVs. AD and BM-EVs were purified by ultracentrifugation. Autologous cell therapies were administered three times intravenously; immediately after kidney transplantation, 4 and 8 weeks, whereas donor-derived cell therapies were administered once intravenously immediately after transplantation. Survival and renal function were monitored. Twelve weeks after kidney transplantation grafts were harvested, infiltrating lymphocytes were analyzed by flow cytometry and histological lesions were characterized. Results: Autologous AD-and BM-MSCs, but not their EVs, prolonged graft and recipient survival in a rat model of kidney rejection. Autologous AD-and BM-MSCs significantly improved renal function during the first 4 weeks after transplantation. The amelioration of graft function could be associated with an improvement in tubular damage, as well as in T, and NK cell infiltration. On the other side, the application of donor-derived AD-MSC was harmful, and all rats died before the end of the protocol. AD-EVs did not accelerate the rejection. Contrary to autologous MSCs results, the single dose of donor-derived BM-MSCs is not enough to ameliorate kidney graft damage.

Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases

“…Experiments by Koch et al indicated that MSC-EVs regulate the immunoreaction to allogeneic kidney transplants to some extent [109]. Significantly different from this, by establishing a rat model of heterotopic kidney transplantation, Jose Ramirez-Bajo et al found that autologous MSCs prolong the survival time of transplants and subjects in the rat model of renal rejection, while EVs do not [110]. This topic is rarely studied, and further research is required before a conclusion can be drawn.…”

Exosomes as New Biomarkers and Drug Delivery Tools for the Prevention and Treatment of Various Diseases: Current Perspectives

“…Exosomebased therapies are currently being studied to specifically silence the immune system toward the graft. Several cell types are candidates for sources of exosomes: mesenchymal stem cells, regulatory T cells, M2 macrophages and immature dendritic cells, which are well-known immunoregulatory cells [141][142][143][144].…”

Efficacy and Safety of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Antibody-Mediated Rejection After Kidney Transplantation- A Single-Arm, Two-Dosing-Regimen, Phase I/II Study

“…Since 2004, when MSCs were introduced to treat graft versus host disease (GvHD) after bone marrow transplantation (7), its therapeutic effect on inflammatory and autoimmune diseases have been widely reported (8). Multiple studies have demonstrated the potential effect of MSCs in kidney transplantation as induction therapy, minimizing calcineurin inhibitors (CNIs), rejection treatment and tolerance induction (9)(10)(11)(12)(13)(14)(15). In addition, preclinical studies have showed that MSCs therapy prevents interstitial fibrosis and tubular atrophy in a chronic rejection model of rat kidney transplantation (16,17).…”