PS15.2: Proteomic evidence of anti senescent reconditioning by mesenchymal stromal cell derived extracellular vesicles in human marginal kidneys during hypothermic oxygenated perfusion.

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Background: Kidneys from extended criteria donors (ECDs) are increasingly utilized to address organ shortages, but their elevated susceptibility to ischemia-reperfusion injury (IRI) poses a significant challenge. Cellular senescence and structural deterioration are key contributors to this vulnerability. Hypothermic oxygenated perfusion (HOPE) has shown promise in improving graft quality, and the addition of mesenchymal stromal cell-derived extracellular vesicles (EVs) may further enhance protective and regenerative outcomes. Methods: Eight human ECD kidneys were perfused ex vivo for 240 minutes using HOPE, with four kidneys receiving stromal cell-derived EVs and four serving as HOPE-only controls. Biopsies were collected at baseline, 180, and 240 minutes. Renal tissue and EVs cargo were analyzed via high-resolution mass spectrometry. Differential protein expression and pathway enrichment analyses were performed. Results: Proteomic analysis identified 2,424 proteins, of which 710 displayed significant time-dependent variation. At 240 minutes, 27 proteins were differentially expressed between the HOPE and HOPE+EVs groups, indicating a specific molecular effect of EVs treatment. Gene ontology enrichment revealed modulation of 21 biological processes, including pathways associated with senescence, oxidative stress, energy metabolism, cytoskeletal organization, and immune response. Proteomic characterization of the EVs confirmed the presence of several regulatory protein kinases linked to these pathways. Immunohistochemistry confirmed reduced p16(INK4a) expression and increased Ki67 in HOPE+EVs-treated kidneys, consistent with anti-senescent and regenerative effects. Conclusions: EVs derived from mesenchymal stromal cells induce a distinct proteomic reprogramming in marginal human kidneys during HOPE, promoting anti-senescent, antioxidant, and pro-regenerative responses. These effects appear to be mediated by EV-associated proteins. Stromal EVs represent a promising therapeutic strategy to recondition ECD kidneys before transplantation. Further in vivo validation is warranted.

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