Mesenchymal stem/stromal cells and their extracellular vesicle progeny decrease injury in post-stenotic swine kidney through different mechanisms.

Novel therapies are needed to address the increasing prevalence of chronic kidney disease. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) augment tissue repair. We tested the hypothesis that EVs are as effective as MSCs in protecting the stenotic kidney, but target different injury pathways. Pigs were studied after 16 weeks of renal injury achieved by diet-induced metabolic syndrome (MetS) and renal artery stenosis (RAS). Pigs were untreated or treated four weeks earlier with intrarenal delivery of autologous adipose tissue-derived MSCs (107) or their EVs (1011). Lean pigs and sham RAS served as controls (n=6 each). Stenotic-kidney function was studied in-vivo using CT and MRI. Histopathology and expression of necroptosis markers (RIPK-1 and RIPK-3), inflammatory, and growth factors (angiopoeitin-1 and VEGF) were studied ex-vivo. Stenotic-kidney glomerular filtration rate and blood flow in MetS+RAS were both lower than Lean, and increased in both MetS+RAS+MSC and MetS+RAS+EV. Both MSCs and EV improved renal function, and decreased renal hypoxia, fibrosis, and apoptosis. MSCs were slightly more effective in preserving microvascular (0.02-0.2mm diameters) density, and prominently attenuated renal inflammation. However, EV more significantly upregulated growth-factor expression and decreased necroptosis. In conclusion, adipose tissue-derived MSCs and their EV both improve stenotic kidney function and decrease tissue injury in MetS+RAS by slightly different mechanisms. MSCs more effectively preserved the microcirculation, while EV bestowed better preservation of renal cellular integrity. These findings encourage further exploration of this novel approach to attenuate renal injury.