Renal regenerative potential of different extra-cellular vesicle populations derived from bone marrow mesenchymal stromal cells

Extra-cellular vesicles (EVs) derived from human bone marrow mesenchymal stromal cells (MSCs) promote the regeneration of kidneys in different animal models of AKI in a manner comparable to the cells of origin. However, due to the heterogeneity observed in the EVs isolated from MSC, it is unclear which population is responsible for the pro-regenerative effects. We therefore evaluated the effect of various EV-populations separated by differential ultracentrifugation (10K population enriched with microvesicles and 100K population enriched with exosomes) on AKI recovery. Only the exosomal-enriched population induced an improvement of renal function and morphology, comparable with that of the total EV population. Interestingly, the 100K EVs exerted a pro-proliferative effect on murine tubular cells, both in vitro and in vivo. Analysis of the molecular content from the different EV populations revealed a distinct profile. The 100K population for instance was enriched in specific mRNAs (CCNB1, CDK8, CDC6) reported to influence cell cycle entry and progression; miRNAs involved in regulating proliferative/anti-apoptotic pathways and growth factors (HGF and IGF-1) that could explain the effect of renal tubular cell proliferation. On the other hand, the EV population enriched in microvesicles (10K), was unable to induce renal regeneration and had a molecular profile with lower expression of pro-proliferative molecules. In conclusion, the different molecular composition of exosome- and microvesicle-enriched populations may explain the regenerative effect of EVs observed in AKI.