Regenerative medicine approaches to the treatment of cardiovascular disease

Ischemic heart disease related myocardial infarction (MI) remains the leading cause of mortality in western countries and increasingly in the rest of the world. However, there are no therapies currently available to directly treat MI-induced death of cardiomyocytes to improve cardiac function in the infarct zone.Cardiac tissue regeneration in the infarct zone using stem cells is a promising approach for directly treating MI. However, several challenges remain in this area including poor cell retention at the injection site, dismal cell viability, and inadequate differentiation into cardiomyocytes (particularly for non-pluripotent stem cells). Although pluripotent stem cells, like embryonic stem (ES) and induced pluripotent stem (iPS) cells, possess the best capacity to differentiate into cardiomyocytes and other cardiac cells, they can also form tumors after injection. We have developed novel coaxial electrospray and 3D nonplanar microfluidic technologies to encapsulate mouse ES cells for miniaturized 3D culture in vitro. This technology improves ES cell survival and proliferation, allowing the ES cells to merge and form one cell aggregate in each microcapsule. Cells in these aggregates display higher pluripotency for further direct differentiation into cardiac lineage than the cells cultured under conventional 3D or 2D conditions. After pre-differentiation into the cardiac lineage the aggregates were further encapsulated in an alginate-chitosan micro-matrix (ACM) for intramyocardial implantation to treat MI in a mouse model. The ACM encapsulated cells were found to differentiate into cardiomyocytes in the infarct zone, which increases survival time and cardiac structure/function. Remarkably, while injection of nonencapsulated cell aggregates would result in tumor formation (87.5%), it was not observed at all with ACM encapsulated cells.The use of this technology to assist with the delivery of stem cells may have translational value of the treatment of MI in patients.