Engineering cardiac regeneration using stem cells: Cellular sources, differentiation signatures, targeted delivery, and functional recovery.

Cardiovascular diseases remain the leading cause of mortality worldwide, and the limited regenerative capacity of the adult heart continues to delay functional recovery, resulting in myocardial injury. Stem cell-based therapies offer a promising avenue for cardiac repair through mechanisms that include cardiomyogenic differentiation, paracrine signaling, angiogenic stimulation, and immunomodulation. Although pluripotent stem cells, mesenchymal stem cells, and cardiac progenitor cells have demonstrated significant benefits in preclinical models, clinical translation has yielded modest functional improvements, mainly due to poor cell retention, electrical and structural immaturity of transplanted cells, immune-mediated clearance, and concerns regarding tumorigenicity and arrhythmogenicity. Therapeutic efficacy largely derives from extracellular vesicles, secreted microRNAs, pro-survival cytokines, and other bioactive substances released by cells. Direct replacement of cardiomyocytes is challenging because the host tissue environment limits the acceptance and stable integration of exogenous cells. Novel engineered cardiac patches, biomaterial-assisted cell delivery, gene-edited progenitor transplantation, exosome therapeutics, and cell-free therapy are improving safety, the plausibility of cell transplantation, and the precision of tissue targeting. Despite those biotech improvements, there are still significant obstacles to restoring permanent, clinically meaningful cardiac function. Regenerative stem cell and cell-free technologies will have the greatest potential for myocardial repair if integrative approaches to regenerative biology, biomaterial engineering, and immunomodulation are used.