Introduction:Myocardial ischemia (MI) is a leading cause of morbidity and mortality worldwide. Mesenchymalstemcell(MSC) treatment of MI reduces scar size and improves perfusion and heart function. While few MSCs are retained, improvements followingMSC-based therapies have been attributed to paracrine effects, in whichexosomes(Exos) may play a major role.HYPOTHESIS:The effectiveness ofby MSC-derived exosomes (MSC-Exos) is sex-dependent.Methods:MSC-Exos were isolated from conditioned medium via ultracentrifu-gation. Flow cytometry analysis, transmission electron microscopy, and nanosight were used to identify and quantifyexosomes. Human inducedpluripotentstemcells (hiPSCs) and human-MSCs (hMSCs) were co-cultured under hypoxic (1% O2) conditions. We evaluated the effects of male and female MSC-Exos on differentiation and proliferation of hiPSCs by qPCR and MTT assays, respectively. Exosomal microRNAs (miRs) were subjected to microarray profiling analysis and WNT signaling was assessed by Western blot.Results:Most MSC-Exos were ~50-150 nm in diameter and expressed CD9, CD63, and CD81. Female MSC-Exos increased hiPSC expression of NKX2.5 and WNT signaling compared to treatment with male MSC-Exos. Similarly, hiPSCs proliferation was stimulated by both female and male MSC-Exos, with female MSC-Exos exerting a greater effect. Expression of miR302b and miR181b were significantly different in female compared to male MSC-Exos .Conclusions:We demonstrated that female MSC-Exos have a greater effect on hiPSC differentiation and proliferation than male MSC-Exos. We predict that miR302b promotes differentiation of hiPSCs into cardiac progenitor cells in a sex-specific manner and that miR181b enhances proliferation through activating the WNT signaling pathway of hiPSCs, potentially increasing cardiomyocyte proliferation.