Introduction to the special issue on stem cells and their products for cardiac repair and regeneration

Myocardial infraction (MI) is one of the most frequent causes of heart failure (HF). A permanent loss of cardiomyocytes (CMs) and irreversible damage of contractile myocardial tissue caused by MI cannot be compensated by current treatments. More than 2 decades ago, cells (i.e. myoblasts), for the first time, were injected into a patient with severe HF as a therapy. This pioneering study started an era for the multiple experimental and clinical explorations of cardiac cell therapy, aiming to repair damaged myocardial tissue. A large and growing body of evidence from various animal models of heart injury demonstrate the efficacy of cell therapy and suggest two major mechanisms for promoting cardiac repair. These are stimulation of innate repair mechanisms by paracrine effects and/or replacement of the lost myocardium. However, the outcomes of clinical trials are controversial in the extent of benefits, suggesting that there is far more to understanding cell therapy than knowing facts. It is necessary and critical to perform additional basic research for a better understanding of how cell therapy works and to develop more effective strategies. Recently positive outcomes from experimental and clinical studies using human pluripotent stem cell (hPSC)-derived CMs, mesenchymal progenitor cells, and cell-secreted products (extracellular vesicles (EVs) and paracrine factors) continuously fuel enthusiasm in cell- and cell product-based therapy for ischemic heart disease and HF. However, the efficacy and safety of these strategies, particularly the cell quality control, their ability in stimulating myocardial remuscularization by replacement and/or promoting endogenous CM generation, and mechanisms of action await to be adequately addressed before moving to clinical application. In this special issue, we have invited experts in the field of stem cells and cell products for cardiac repair and regeneration to write reviews on topics, specifically, focusing on: (1) metabolic control of hPSC-derived CM generation and maturation as well as large-scale production and quality control of these cells; (2) most recent progress of hPSC-derived cardiac cells and cell-secreted productions in preclinical, particularly in large animal models, and clinical studies for cardiac repair and regeneration; (3) optimization in engineering stem cells and cell products for cardiac repair; and (4) challenges and clinical perspectives of cell- and cell product-based therapies for promoting cardiac repair and regeneration. In summary, this special issue will serve as a platform to promote “conversations” among investigations on these critical topics, highlight the gaps for the translation of findings from preclinical studies to clinical application, and provide perspectives for achieving the goal of repair and regeneration of damaged myocardium.