Ultrasound-Targeted Microbubble Destruction-Mediated Co-Delivery of <i>Cxcl12</i> (<i>Sdf-1alpha</i>) and <i>Bmp2</i> Genes for Myocardial Repair

Abstract

Acute myocardial infarction (AMI) is a serious threat to human health. Stem cells can serve as ideal seed cells for myocardial repair and regeneration; however, insufficient homing to the infarcted areas and poor myocardial differentiation limit their further clinical application. Chemokine (C-X-C motif) ligand 12 (CXCL12) is an important stem cell homing factor, and Bone morphogenetic protein-2 (BMP2) is a differentiation-promoting factor. In this study, we designed microbubbleadenovirus complexes and investigated the functional benefit of co-delivery of <i>Cxcl12</i> and <i>Bmp2</i> genes in adenoviral vectors by ultrasound-targeted microbubble destruction (UTMD) for myocardial repair in AMI rats. By transfection of rat bone marrow mesenchymal stem cells (BMSCs), high transfection efficiency was achieved under ultrasound irradiation, and successful myocardial differentiation of the transfected BMSCs was induced after ultrasound-mediated-transfection of <i>Bmp2</i> <i>in vitro</i>. In the AMI rat model, co-delivery of <i>Cxcl12</i> and <i>Bmp2</i> at a ratio of 2:1 may result in significantly higher myocardial repair efficacy compared to transfection of <i>Cxcl12</i> or <i>Bmp2</i> only. Higher myocardial repairing efficacy was achieved with co-delivery of <i>Cxcl12</i> and <i>Bmp2</i> at a ratio of 2:1 than using a ratio of 1:1 or 1:2, as evidenced by smaller infarction size, higher micro-vessel density, and better recovery of cardiac function at 28 days after treatment. Hence, UTMD-mediated co-transfection of <i>Cxcl12</i> and <i>Bmp2</i> significantly promoted the repair/regeneration of the infarcted myocardium, thereby providing a promising approach for the repair of cardiac injury.