Myocardium-targeted transplantation of PHD2 shRNA-modified bone mesenchymal stem cells through ultrasound-targeted microbubble destruction protects the heart from acute myocardial infarction

Ultrasound-targeted microbubble destruction (UTMD) is a promising approach to facilitate the precise delivery of bone marrow stem cells (BMSCs) to the ischemic myocardium. However, stem cell therapy for ischemic myocardium is challenging due to the poor survival of transplanted stem cells under severe ischemic conditions. In this study, we investigated whether myocardium-targeted transplantation of prolyl hydroxylase domain protein 2 (PHD2) shRNA-modified BMSCs by UTMD increases the viability of grafted cells, and enhances their cardioprotective effects in acute myocardial infarction. Methods: BMSCs were transduced with lentiviral PHD2 shRNA, and a novel microbubble formulation was prepared by a thin-film hydration method. In rats, BMSCs with or without PHD2 shRNA modification were transplanted by UTMD after inducing acute myocardium infarction. Effects of PHD2 shRNA on BMSC survival, myocardial apoptosis, angiogenesis, and cardiac function were evaluated. In vitro, anti-apoptotic effects and its mechanisms of PHD2 silencing on BMSC and BMSC-conditioned medium on H9C2 cell were detected. Results: PHD2 shRNA-modified BMSC transplantation by UTMD resulted in increased BMSC survival, reduced myocardial apoptosis, reduced infarct size, increased vascular density, and improved cardiac function compared to the control vector-modified BMSC transplantation by UTMD. PHD2 silencing increased BMSC survival through a HIF-1α-dependent mechanism. The decrease in cardiomyocyte apoptosis by conditioned medium from PHD2 shRNA-treated BMSCs was due to an increase in the expression of insulin-like growth factor (IGF)-1. Conclusions: The delivery of PHD2 shRNA-modified BMSCs by UTMD promoted grafted cell homing and activity, and increased myocardial angiogenesis in the infarcted heart, leading to improved cardiac function. This combination may provide a promising strategy for enhancing the effectiveness of stem cell therapy after acute myocardial infarction.