Nanoparticle-assisted targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy.

Rationale: The cardiac scar is an area rich in collagen. It is populated by myofibroblasts and lacks Connexin 43 expressing cardiomyocytes. Myocardial infarctions have so far proven little amenable to gene- and cell-based therapeutic interventions. Our aim was to establish an experimental approach with translational potential for effective cell-based gene therapy of the cardiac scar. Methods: We have developed a targeting strategy for myocardial infarctions by grafting ex vivo lentivirus-transduced and magnetic nanoparticle-loaded embryonic cardiac myofibroblasts into mouse hearts with magnetic steering. Results: Our approach yielded highly efficient targeting and cell grafting into the cardiac scar. Engraftment rates of myofibroblasts proved very high (30% of injected cells) due to cell proliferation and a low apoptosis rate. We also demonstrate that grafting lentivirus-transduced Connexin 43 overexpressing myofibroblasts into the lesion resulted in increased Connexin 43 protein content and strong protection against ventricular arrhythmias in vivo, as their incidence was reduced by ~ 50% at 2- and 8 weeks after myocardial infarction. Conclusion: The combination of ex vivo gene and in vivo cell therapy, along with magnetic steering of cardiac myofibroblasts, enables, efficient targeting of the cardiac scar and can even modulate its functional properties.