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EX VIVO MESENCHYMAL STEM CELL THERAPY PROTECTS VASCULAR NETWORKS FROM ISCHEMIA REPERFUSION INJURY
Presenter: Presenter: Mark McRae, MD
Co-Authors: McRae MH; Ham MJ; Soares M; Wilson SC; Lotfi P; Lalezarzadeh F; Ojo CO; Saadeh PB; Ceradini DJ
NYU Medical Center

Background: Endothelial failure is a common endpoint of various clinical scenarios including sepsis, flap failure, ischemia-reperfusion injury & chronic edema. While therapies focus on correcting oft-disparate etiologies, strategies to protect the vascular barrier could minimize a variety of adverse outcomes. As mesenchymal stem cells (MSCs) have immunomodulatory & regenerative properties, we hypothesized that MSCs can be exploited as a strategy to mitigate endothelial failure following cytotoxic insults.

Methods: Using a model of ischemia-reperfusion injury (IRI), MSCs and endothelial cells (ECs) were co-cultured; endothelial-related gene expression profiles were generated 6hrs post-reperfusion. Following IRI, leukocyte adhesion was assessed to determine the effect of MSCs on endothelial inflammation. In an in vivo model of VCA, Brown Norway rat allografts were seeded with Lewis rat MSCs ex vivo and transplanted into Lewis rats. Revascularization and limb perfusion were assessed by laser doppler. Explanted grafts were analyzed in the early post-operative period (Results: Following IRI, MSC co-culture increased EC expression of essential factors VE-CAD, eNOS, and FLT-1 (230%, 330%, 200%, respectively, p < 0.01 for all), and decreased inflammatory factors MCP-1 and ICAM-1 (83%, 47% reduction, respectively, p<0.05 for all) when compared to EC-only culture. Functionally, this correlated in decreased leukocyte adhesion (49%, p <0.01). In situ, MSC-seeded flaps demonstrated enhanced vascularity compared to controls (209% vascular flux increase, p<0.02). Explanted flaps featured MSCs within the perivascular space, decreased inflammatory markers (85% reduction in ICAM-1, 74% reduction in MCP-1, p<0.01) in the early post-operative period.

Conclusion: MSCs protect the endothelial barrier in response to cytotoxic injury from IRI. Our ex vivo MSC delivery strategy is easily translatable and has potential to reduce adverse vascular sequelae.


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