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Mesenchymal stem cells (MSCs) are a promising cell resource for treating ischemic diseases partially through paracrine effects.One of the major obstacles for MSCs treatment is the poor survival rate and low efficiency of transplanted stem cells due to ischemic or inflammatory environments.Gremlin1 (GREM1),a regulator of growth,differentiation and development,has been identified as a novel proangiogenic factor.However,the role and mechanism of GREM1 in MSCs are not clearly.We therefore assessed the putative beneficial effects of GREM1 on MSCs-based therapy for hindlimb ischemia.The lentiviral vector,EF1a-GREM1,was constructed using the Multisite Gateway System and used to transduce MSCs.In vitro studies found increased survival of GREM1-MSCs to H2O2which is consistent with the activation of caspase3.Conditional medium from GREM1-MSCs (GREM1-MSC-CM) increased the anti-apoptotic effect of human umbilical vein endothelial cells (HUVECs),which was attenuated by treatment with the PI3K/Akt pathway inhibitor LY294002.In vivo,the MSCs modified with GREM 1 could significantly increase the blood perfusion of ischemic hindlimb of mice model,which was correlated to an improved survivability of MSCs.This study provides the concept that overexpression of GREM1 in MSCs provide greater therapeutic effects against ischemia compared to wild-type MSCs through enhancing the survival of MSCs and ECs,which may provide new tools for the studies of ischemic diseases treatment.