Urine-derived stem cell extracellular vesicles promote recovery from acute kidney injury in mice and human kidney organoids.

Extracellular vesicles (EVs) contain RNA, protein, lipids, and other molecules from their parental cell type, which led to the hypothesis that urine-derived stem cell EVs (USC-EVs) could have potent regenerative effects in the setting of acute kidney injury (AKI). We tested this hypothesis in two different in vitro AKI models and an in vivo AKI model. To test USC-EVs ability to recover human kidney cells from nephrotoxicity, HK-2 human proximal tubular epithelial cell line and human kidney organoids derived from induced pluripotent stem cells were treated with 5 μM cisplatin for 48 h followed by 10 μg USC-EVs for 48 h. We also tested USC-EVs in the unilateral nephrectomy followed by ischemia reperfusion model (UNIRI) AKI model to explore systemic effects in animals. USC-EV treatment of human kidney cells resulted in increased cellular proliferation (P ≤ 0.0001), decreased cytotoxicity (P < 0.0001), and lowered oxidative stress (P ≤ 0.01) as compared with cisplatin alone groups. In mouse models, we found improved pathology as well as reduced kidney injury marker KIM-1 expression in the USC-EV treated group as compared with the UNIRI alone group. Analysis of USC-EV miRNA-targeting pathways was associated with epithelial cell proliferation, migration, and positive regulation of MAPK signaling pathway. As predicted by this analysis, we found increased phosphorylation of the MAPK downstream target ERK1/2 in USC-EV-treated HK-2 cells. This study suggests that much of the reported benefit of USCs is due to their EVs and supports further development of USC-EVs as a potential next-generation therapeutic for AKI.NEW & NOTEWORTHY Urine-derived stem cell extracellular vesicles (USC-EVs) increased proliferation while lowering apoptosis and lipid peroxidation in human kidney cells and organoids treated with toxic chemotherapy. In the acute kidney injury (AKI) model mice, we found lowered inflammation, tubular dilation, casts, and kidney injury marker neutrophil gelatinase-associated lipocalin (NGAL) with USC-EV treatment. The USC-EVs carry microRNA cargo that bioinformatic tools predict will affect multiple pathways, including the MAPK cascade. Altogether, our results suggest that USC-EVs may improve recovery from AKI.