Between Promise and Limitation: Hydrogel-Delivered Cardiac Atrial Appendage Stem Cells for Myocardial Repair

Abstract

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide and frequently leads to heart failure due to the irreversible loss of cardiomyocytes. Although advances in clinical management have improved survival, no effective therapy currently exists to restore cardiac function following MI. This doctoral thesis investigated the regenerative potential of cardiac atrial appendage stem cells (CASCs) embedded in an elastin-like recombinamer (ELR) hydrogel as a novel therapeutic strategy for myocardial repair. CASCs are characterized by cardiomyogenic differentiation potential and pro-angiogenic paracrine activity, while the ELR hydrogel provides a biocompatible and biodegradable scaffold that may enhance cell retention within the infarcted myocardium. To support reliable therapeutic evaluation, the rat MI model was refined to improve experimental robustness and reduce animal burden. In addition, an echocardiography-guided injection protocol was optimized to enable precise and clinically relevant therapy delivery. In an acute MI setting, the combination of CASCs and ELR hydrogel resulted in greater functional improvement than CASCs alone and demonstrated complementary molecular mechanisms that integrated the effects of both therapies. However, when treatment was administered at a later stage following MI, functional benefits were reduced and the molecular response differed substantially from that observed after acute administration. Furthermore, CASCs were no longer detectable one week after injection, suggesting that limited cell retention reduced therapeutic efficacy. This effect was likely influenced by infarct severity, the stage of left ventricular remodeling, and immune responses. Overall, these findings demonstrate that the effectiveness of CASCs–ELR hydrogel therapy is strongly influenced by the timing of administration and the post-infarction myocardial environment. The study highlights the importance of optimizing therapeutic timing, delivery strategies, and cell retention to advance regenerative therapies for MI.