Myocardial Regenerative Capacities of the Cardiac Atrial Appendage Stem Cell

Abstract

Heart failure as a consequence of myocardial infarction (MI) is one of the major causes of global morbidity and mortality. Stem cells promise to replace the damaged or lost cardiac muscle with functional healthy tissue. However, only moderate therapeutic effects were observed in clinical trials with various stem cell types, likely due to their limited cardiomyogenic differentiation. Recently a new cardiac stem cell population was discovered, called the cardiac atrial appendage stem cell (CASC). These CASCs have typical stem cell properties and possess a superior in vitro myocardial differentiation potential compared to other stem cell types. This project further explored the contribution of CASCs to myocardial regeneration. The safety and therapeutic benefit of CASC transplantation in a minipig MI model was established. Improvement of both regional and global left ventricular function together with a reduction in scar mass were associated with extensive cell engraftment and the formation of fully differentiated cardiomyocytes with a mature contractile profile. Moreover, CASCs showed electromechanical integration into the host myocardium without observations of cardiac arrhythmias. In the second part of this study, it was shown that CASCs do not contribute to neovascularization by differentiation into vascular cells, but by the secretion of numerous angiogenic growth factors. Combined myogenesis and angiogenesis enhances the therapeutic potential of CASCs, making them highly suited for the treatment of ischemic heart disease. Finally, the effect of the inflammatory infarct environment on CASCs was investigated. CASC viability was not affected by inflammatory conditions and they showed a low immunogenic profile and immunomodulatory properties. These results might pave the way for allogeneic stem cell transplantation, which would allow development of an ‘off-the-shelf’ cell-based therapy. In conclusion, this study yielded essential proof of the safety and therapeutic efficacy of CASC transplantation after MI and provides important insights for the further development of the therapeutic application of CASCs in ischemic heart disease patients.