Cardiac Atrial Appendage Stem Cells and Paracrine Mechanisms for Myocardial Repair

Abstract

The incidence of heart failure secondary to myocardial infarction (MI) raises dramatically with age. After MI, the pumping efficiency of the heart is severely impaired due to extensive loss of cardiac tissue and the formation of a noncontractile scar. Current medicine has been useful in improving the patient’s quality of life, but it does not restore cardiac function and simply delays the progression towards heart failure. In the last decade, stem cell transplantation has been extensively discussed, although the exact approach and ideal stem cell for cardiac regeneration are yet to be determined. Recently, the research group at the Jessa Hospital reported the existence of a new type of cardiac stem cell present in the atrial appendage of patients with ischemic heart disease. Hence the name “Cardiac Atrial appendage Stem Cells” or simply, “CASCs”. After promising in vitro data regarding their isolation and basic characteristics, the prospects of CASCs for clinical settings are further explored in this thesis. This project sheds light on the role of a specific signal transduction axis in the migration process of CASCs inside an innovative threedimensional collagen model implemented in our laboratory. Furthermore, this work provides a comprehensive view on the biological properties of CASCs during long-term in vitro cultivation by continuously monitoring their growth kinetics, immunophenotype, aging processes and cardiomyogenic differentiation potential. Additionally, this study reports the successful establishment of a humanized culture method that is suitable for the large-scale ex vivo expansion of CASCs for clinical purposes. In the last part, a preclinical animal model was implemented to investigate the engraftment and in vivo cardiac differentiation of CASCs. The procedure of MI induction was optimized in adult Gottingen minipigs and a step-by-step approach was employed to achieve a successful transplantation protocol for CASC delivery in the infarcted heart. The results described in this manuscript provide important insights for the future design of a clinical oriented protocol with stem cells, or their released agents, to promote cardiac regeneration and repair in patients after MI.