NAMPT overexpression enhances the regenerative potential of mesenchymal stromal cell-derived extracellular vesicles in experimental AKI.

Acute kidney injury (AKI) is a serious condition marked by a rapid decline in renal function, often leading to long-term complications. Mesenchymal stromal cells (MSCs) and their derivatives, including conditioned medium (CM) and extracellular vesicles (EVs), show promise as regenerative therapies. However, the comparative efficacy of CM and EVs and the development of clinically translatable interventions remains underexplored. This study systematically compared the renoprotective effects of CM and EVs derived from human umbilical cord MSCs in a murine cisplatin-induced AKI model, using a therapeutically feasible dose. Both treatments improved renal function, reduced histological damage, preserved mitochondrial integrity, energy metabolism, and antioxidant response. Notably, EVs induced the greatest proliferative response in renal tubular cells. To further enhance the regenerative potential of EVs, we engineered MSCs to overexpress nicotinamide phosphoribosyltransferase (NAMPT), a metabolic enzyme that plays a key role in NAD(+) biosynthesis. NAMPT-transfected MSCs released NAMPT-enriched EVs, which more effectively enhanced cell viability, reduced apoptosis, and protected mitochondria in cisplatin-damaged tubular cells in vitro compared to EV-GFP. In mice with AKI, NAMPT-enriched EVs improved renal function and repaired damage by enhancing renal NAMPT and NAD(+) levels, promoting tubular cell regeneration. Mechanistically, the amelioration of mitochondrial function was related to increased PGC1α and SIRT3 and consequently SOD2 and ATP5i expression. These findings highlight the therapeutic potential of EVs, particularly NAMPT-enriched EVs, in renal repair, supporting their promise as a clinically translatable approach for promoting recovery from AKI and other kidney diseases.