Engineering Therapeutic Mesenchymal Stem Cells to Overexpress HIF1α
Reseachers here demonstrate that engineering the mesenchymal stem cells provided in a cell therapy to overexpress HIF1α produces regeneration in a pig model of heart failure. The mechanisms involved are up for debate, as they may or may not involve an extension of survival of the stem cells following transplant, versus a shift in cell signaling. Mesenchymal stem cells do not survive long in most such treatments, and their beneficial effects are the result of signals secreted in the short time they are present in tissues. Given the feasibility of engineering cells in vitro in any number of ways, this is a logical next step for the industry, now that first generation cell therapies are so well established.
Recent preclinical investigations and clinical trials with stem cells mostly studied bone-marrow-derived mononuclear cells (BM-MNCs), which so far failed to meet clinically significant functional study endpoints. BM-MNCs containing small proportions of stem cells provide little regenerative potential, while mesenchymal stem cells (MSCs) promise effective therapy via paracrine impact. Genetic engineering for rationally enhancing paracrine effects of implanted stem cells is an attractive option for further development of therapeutic cardiac repair strategies. Non-viral, efficient transfection methods promise improved clinical translation, longevity and a high level of gene delivery.
Hypoxia-induced factor 1α (HIF1α) is responsible for pro-angiogenic, anti-apoptotic and anti-remodeling mechanisms. Here we aimed to apply a cellular gene therapy model in chronic ischemic heart failure in pigs. A non-viral circular minicircle DNA vector was used for in vitro transfection of porcine MSCs (pMSC) with HIF1α (pMSC-MiCi-HIF-1α). pMSCs-MiCi-HIF-1α were injected endomyocardially into the border zone of an anterior myocardial infarction one month post-reperfused-infarct.
Animals underwent treatment one month after infarction, which more aptly reflects realistic clinical application, but arguably complicates successful outcomes, because the initial repair and immunological processes start immediately at the onset of infarction. Nonetheless, pMSC-MiCi-HIF-1α significantly reduced myocardial scar size and improved cardiac output. Our results thus underline the potential as a therapeutic concept.