P0146MESENCHYMAL STEM CELLS AND THEIR EXTRACELLULAR VESICLES PROGENY DECREASE RENAL INJURY IN EXPERIMENTAL SWINE RENAL ARTERY STENOSIS THROUGH DIFFERENT MECHANISMS

Abstract

Abstract Background and Aims 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. EVs have practical benefits, but their efficacy relative to MSCs is incompletely understood. We tested the hypothesis that EVs are as effective as MSCs in protecting the stenotic kidney but target different injury pathways. Method 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 a single intrarenal delivery of autologous adipose tissue-derived MSCs (1 × 107) or EVs (1 × 1010). Lean pigs and sham RAS served as controls (n=6 each). Stenotic kidney function was studied in-vivo using CT. Histopathology and expression of necroptosis markers (RIPK-1 and RIPK-3), inflammatory and growth factors (angiopoeitin-1 and VEGF) was studied ex-vivo. Results Stenotic-kidney glomerular filtration rate and blood flow in Mets+RAS were both lower than Mets, increased in Mets+RAS+MSCs, and further improved in Mets+RAS+EV. Both MSCs and EVs improved renal function, hypoxia, and decreased renal fibrosis and apoptosis. MSC were slightly more effective in preserving microvascular density (0.02-0.2mm in diameter), and prominently attenuated renal inflammation. However, EVs more significantly upregulated growth-factor expression and decreased necropotosis. Conclusion: Adipose tissue-derived MSCs and their EVs both improve stenotic kidney function and decrease tissue injury in Mets+RAS. MSCs more effectively preserve the microcirculation, while EVs bestow better preservation of renal cellular integrity. These findings encourage further exploration of this novel approach to attenuate renal injury.