Paracrine effect of wnt11-overexpressing mesenchymal stem cells on ischemic injury

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 (MSC ^Wnt11). An acute myocardial infarction model in rats was developed by ligation of the left anterior descending coronary artery. MSC ^Wnt11 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 MSC ^Wnt11 compared with transduced control MSC (MSC ^Null). Hypoxia-induced apoptosis and cell death was significantly reduced when CM were co-cultured with MSC ^Wnt11 in a dual chamber system. The cell protection mediated by MSC ^Wnt11 was mimicked by treating CM with conditioned medium obtained from MSC ^Wnt11 and abrogated by Wnt11- and TGFβ2 neutralizing antibodies. Further, animals receiving MSC ^Wnt11 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 MSC ^Wnt11-treated animals. Transplantation of MSC ^Wnt11 improved cardiac function. The release of Wnt11 and other factors from transplanted MSC ^Wnt11 is more likely responsible for protection of native CM at risk.