TA and F were scored from grade 0 to 3 (0, none [<10%]; 1, moderate [10 to 20%]; 2, moderate [20 to 50%]; 3, severe [>50%]). were analyzed by circulation 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. Conclusion EVs 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. models of ischemia/reperfusion (Togel et al., 2005; Chen et al., 2011), and renal allograft rejection (Reinders et al., 2010; Hara et al., 2011; Franquesa et al., 2012; Cao et al., 2013), without adverse events reported. Donor-derived MSCs therapy could be especially interesting due to low immunogenicity when compared with other donor-derived cell types from healthy donors (Lohan et al., 2017). However, autologous MSC therapy could be a safer choice to avoid immune responses. In addition, one of the difficulties is to find the most appropriate stem cell type, since proliferation capacity and secretion of secreted paracrine factors depend around the cell type. Loratadine Bone marrow-MSCs (BM-MSCs) are the most widely studied; however, they are not usually the most interesting option. The immunomodulatory properties of MSCs from different adult human tissues; adipose-derived (AD), umbilical cord blood (CB), and cord Whartons jelly (WJ), showed an comparative 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 MAP2 different levels of angiogenic capacity (Hsiao et al., 2012). Previous studies showed that in addition to cell contact, the action of MSCs is due Loratadine to paracrine signaling induced by the secretion of cytokines, growth factors and extracellular vesicles (EVs). However, their mechanisms of action remain unclear. EVs are tiny membrane-enclosed droplets released by cells through membrane budding and exocytosis and are composed of several cytoplasmatic components. They symbolize a cell-cell paracrine/endocrine communication mechanism allowing the transfer of inflammatory cytokines, growth factors and microRNAs which can regulate the proliferation, maturation, and migration of different types of immune cells (Seo et al., 2019). MSC-EVs could reproduce the immunomodulatory functions of MSCs targeting T cells (Blazquez et al., 2014; Del Fattore et al., 2015), B cells (Budoni et al., 2013) and NK cells (Di Trapani et al., 2016) and reduce the production of Loratadine pro-inflammatory cytokines (Ma et al., 2019). Besides, the MSC-EVs compared with the MSCs are a safe cell-free alternate with advantages regarding immunogenicity and tumorigenicity. In this study, we show for the first time a full comparison of the therapeutic effect of AD- and BM-MSC and their EVs within autologous or donor-derived settings in a rat model of chronic kidney allograft rejection. Materials and Methods Animals Male Lewis rats received male either Lewis Loratadine or Fischer-344 (Fisher) grafts for syngeneic and donor-derived kidney transplants, respectively. Fisher and Lewis Loratadine strains differ partially at major histocompatibility complexes and various non-MHC loci, conferring a poor histocompatible combination. The animals were kept at a constant temperature, humidity, and at a 12-h light/dark cycle with free access to water and rat chow. The study was approved by and conducted according to the guidelines of the local animal ethics committee (Comit tic dExperimentaci.