The outcome of cell therapy in older recipients is determined by a combination of age effects on the donor cells and on the recipients' endogenous responses. Donor cell age and recipient age are equally important contributors to the outcome of cell therapy; thus, novel biointerventions will need to target both components of the process.

To increase the accessibility of myogenic cells for cell therapy in the infarcted heart, we identified conditions to improve the reproducible conversion of bone marrow mesenchymal stromal cells (BMSCs) into myogenic cells. Such cells may permit functional regeneration following a myocardial infarction. BMSCs derived from green fluorescent protein (GFP) transgenic rats were co-cultured with neonatal rat cardiomyocytes (1:1, 1:10, 1:20, and 1:40 ratios) for 7 days. Some BMSCs contracted synchronously with the neonatal cardiomyocytes, and exhibited action potentials that were confirmed with current clamp recordings. The myogenic phenotype of the BMSCs was confirmed by immunohistochemical staining and flow cytometry (antibodies against cardiac specific alpha-sarcomeric actinin, Troponin I, MEF-2C). An increase in the number of BMSCs expressing cardiac markers correlated with increasing numbers of neonatal cardiomyocytes in the culture. When BMSCs were co-cultured with DiI-labeled neonatal cardiomyocytes, a small percentage of GFP/DiI/Troponin I triple-positive cells were observed after 7 days. This type of myogenic conversion increased nearly twofold when BMSCs were co-cultured with apoptotic (TNF-alpha-treated) cardiomyocytes. BMSCs co-cultured with cardiomyocytes acquired a functional myogenic phenotype in a dose-dependent manner. Myogenic conversion increased when the BMSCs were cultured with apoptotic cells.

Cardiac cell therapies offer distinct and exciting advantages over current treatments to prevent postinfarction heart failure because they can reverse ventricular remodeling and improve function, but only if the implanted stem cells contribute biological functions and achieve prolonged engraftment within the hostile environment of the damaged heart. Unfortunately, function is diminished in autologous stem cells isolated from older patients and those with comorbidities, and so clinical trials testing the implantation of healthy, allogeneic bone marrow-derived stromal cells (MSCs) isolated from young donors are currently underway. MSCs are unique because, in addition to exerting paracrine effects that restore blood flow and recruit endogenous stem cells to the infarct, they exhibit immune-modulating properties in culture that-if retained after allogeneic implantation-imply the cells may escape immune recognition within the heart. At present, the scope of MSC immune modulation after implantation is unclear.