Abstract
BackgroundMesenchymal 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.MethodsThe 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.ResultsAutologous 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.ConclusionEVs treatments did not exert any benefit in our experimental settings. In the autologous setting, BM-MSCs prompted as a potentially promising therapy to improve kidney graft outcomes in rats with chronic mixed rejection. In the donor-derived setting, AD-MSC accelerated progression to end-stage kidney disease. Further experiments are required to adjust timing and dose for better long-term outcomes.
Highlights
Patient survival after kidney transplantation has improved over the past decade due to the optimization of immunosuppressive strategies
We show for the first time a full comparison of the therapeutic effect of AD- and bone marrow (BM)-mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) within autologous or donor-derived settings in a rat model of chronic kidney allograft rejection
AD-MSCL and their EVs showed worse results compared to BM-MSCL and their EVs
Summary
Patient survival after kidney transplantation has improved over the past decade due to the optimization of immunosuppressive strategies. The immunomodulatory properties of MSCs from different adult human tissues; adipose-derived (AD), umbilical cord blood (CB), and cord Wharton’s jelly (WJ), showed an equivalent potential to suppress T-cell proliferation (Ammar et al, 2015; Pleumeekers et al, 2018) and a different capacity for differentiation (Liu et al, 2007), secretion of different paracrine factors, as VEGF-D, IGF-1, IL-8, and IL-6, that contributes to different levels of angiogenic capacity (Hsiao et al, 2012). 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
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