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Vascularized composite allotransplantation (VCA) is successfully used for reconstruction of major defects of the upper extremity and face. Both rejection and graft vasculopathy (GV) seriously endanger long-term outcomes, eventually leading to graft failure. GV remains widely unexplored in VCA, and so does the role of adipose-derived stromal cells (ASCs) in acute rejection.ASCs were isolated from donors, characterized and their immunomodulatory capacity investigated. Systemic (SASC) versus local intragraft (LASC) ASC administration was evaluated for therapy of acute rejection and GV in fully mismatched rat hind-limb transplants after discontinuation of immunosuppression (FK-506). Tissues (skin/muscle/vessels) and blood samples were taken prior and after therapy for histopathology (H&E; Elastin van Gieson; von Willebrand factor [vWF]) and cytokine analysis (Multiplex).ASCs (CD45-CD29+CD90+) suppressed alloresponse in vitro and reduced pro-inflammatory cytokine levels in mixed lymphocyte reactions (IL-α, IL-β, IL-2, GM-CSF). In vivo, ASC administration at grade II rejection significantly delayed progression to grade III (7.57±1.13 days SASC, 7.29±1.11 days LASC vs 2.75±0.7 days Controls; n=23 animals). Significant GV was detected during acute rejection in controls, whereas ASC administration reduced intima/media ratio (IMR) in arterioles of allograft skin and muscle. However, GV did not affect the greater (femoral) vessels. vWF analysis revealed increased expression in femoral vessels of controls, compared to significantly reduced expression after both local and systemic cell therapy, similar to naïve vessels.Systemic or local ASC therapy significantly reduces progression of onset acute rejection in VCA through attenuation of alloresponse and suppression of pro-inflammatory cytokines. GV was observed during acute rejection in small arterioles, but not in femoral vessels, and was significantly reduced after cytotherapy. vWF was increased in femoral vessels, despite no manifest GV, suggesting early endothelial damage. If vWF is a potential early marker for GV development in VCA needs to be investigated.This study was supported by the Swiss National Science Foundation.