Role of Tumor Necrosis Factor Receptor 1 in Sex Differences of Stem Cell Mediated Cardioprotection

Background: Mesenchymal stem cells (MSCs) hold great therapeutic potential for the repair and regeneration of ischemic tissue, possibly through the release of beneficial paracrine factors. Sex differences have been observed in the paracrine function of MSCs. Female stem cells produce lower proinflammatory cytokines and higher levels of growth factors compared with their male counterparts. Ablation of tumor necrosis factor receptor 1 (TNFR1) increases protective growth factor production by male, but not by female, MSCs. We therefore hypothesized the following: (1) that female MSCs would improve myocardial recovery compared with male MSCs after ischemia-reperfusion injury (I/R); and (2) that MSCs isolated from TNFR1 knock out male, but not female, mice, would improve postischemic myocardial recovery compared with their wild type (WT) counterparts. Methods: Male adult Sprague-Dawley rat hearts were subjected to I/R by Langendorff isolated heart preparation. The MSCs were harvested from adult mice and cultured under normal conditions. Immediately prior to ischemia, one million MSCs were infused into the coronary circulation. Cardiac functional parameters were recorded continuously. Results: Pretreatment with MSCs from either sex significantly increased postischemic myocardial recovery as evidenced by improved left ventricular developed pressure, contractility, and rate of relaxation. Infusion with female MSCs was associated with a greater degree of myocardial recovery after I/R compared with male MSCs. The TNFR1 deficiency increased the degree of myocardial recovery associated with male MSCs, but not with female MSCs. No additional cardioprotection was observed when TNFR1 was ablated in female MSCs. Conclusion: Sex differences influence the cardioprotective effects of both WT and TNFR1 ablated MSCs.