Localized Co-delivery of Serca2a and Cx43 Genes Combined With Bone Marrow Mesenchymal Stem Cells Restores Rat Ischemic Cardiac Mechano-electrical Function

Abstract Aim: Significantly reduced expression of Ca2+-ATPase 2a (SERCA2a) and Connexin 43 (Cx43) which play important roles in regulating mechano-electrical function was found in an ischemic heart. Bone marrow mesenchymal stem cells (BMSCs) transplantation brings with a weak improvement of ischemic heart in cardiac contractility and anti-arrhythmias effect. The aim of this study was to recover mechano-electrical function of ischemic heart through combining stem cell therapy with SERCA2a/Cx43 co-delivery by biotinylated microbubbles (BMBs) via ultrasound targeted microbubble destruction (UTMD).Methods: Dual gene-loaded BMBs were developed through conjugating SERCA2a-adenovirous (S-Ad) and Cx43-adenovious (C-Ad) onto BMBs via biotin-avidin linkage. UTMD was used to mediate the local co-delivery of S-Ad and C-Ad into the infarct zone where BMSCs were transplanted. The expression of SERCA2a and Cx43 gene, neovascularization in the infarct area and mechano-electrical function of rats were detected. Results: UTMD-mediated dual gene delivery could significantly enhance the expression of SERCA2a/Cx43 genes in the infarct zone receiving BMSCs transplantation. Significantly improved neovascularization was observed. More importantly, UTMD-mediated dual gene delivery greatly improved cardiac function and reduced arrhythmia in these myocardial infarct (MI) hearts transplanted with BMSCs. Conclusions: BMSCs-based dual gene therapy can effectively improve cardiac mechano-electrical function and reduce arrhythmia in heart with MI. It is necessary to rebuild the gene network in damaged heart rather than supply a single gene. BMSCs transplantation combined with localized dual-gene delivery by UTMD might point out a novel strategy to recover mechano-electrical function of ischemic heart.