Our previous studies have suggested that transduction of Wnt11 directly increases bone marrow-derived mesenchymal stem cells (MSCs) differentiation into cardiac phenotypes. In this study, we investigated whether Wnt11 enhances MSC-mediated cardioprotection via paracrine fashion after acute ischemia. MSCs were harvested from male rat bone marrow and transduced with Wnt11 (MSCWnt11). An acute myocardial infarction model in rats was developed by ligation of the left anterior descending coronary artery. MSCWnt11 were transplanted into the peri-infarct region after acute myocardial infarction. To mimic ischemic injury, cultured cardiomyocytes (CMs) isolated from neonatal ventricles were exposed to hypoxia. ELISA studies indicated that the release of Wnt11 (3.45-fold) as well as transforming growth factor-β2 (TGFβ2) (1.5-fold) was significantly increased from MSCWnt11 compared with transduced control MSC (MSCNull). Hypoxia-induced apoptosis and cell death was significantly reduced when CM were co-cultured with MSCWnt11 in a dual chamber system. The cell protection mediated by MSCWnt11 was mimicked by treating CM with conditioned medium obtained from MSCWnt11 and abrogated by Wnt11- and TGFβ2 neutralizing antibodies. Further, animals receiving MSCWnt11 showed a significant improvement in cardiac contractile function as assessed by echocardiography. Masson trichrome and TUNEL staining showed a significant reduction in infarct size and apoptosis of CM in MSCWnt11-treated animals. Transplantation of MSCWnt11 improved cardiac function. The release of Wnt11 and other factors from transplanted MSCWnt11 is more likely responsible for protection of native CM at risk.
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