Restoring the damaged heart: mechanisms of myocardial repair and regeneration driven by mesenchymal and pluripotent stem cells

Repair and regeneration of the myocardium remain difficult challenges for cardiovascular medicine because of the heart’s limited inherent regenerative capacity, the multifactorial nature of cardiac injury, and the interplay with other organ systems. Mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs) are currently viewed as the two main cellular systems for cardiac regeneration, highly complementary to one another. While MSCs are primarily viewed as microenvironmental modifiers in the context of myocardial repair, they promote angiogenesis, immune modulation, metabolic stabilization, mitochondrial rescue, and anti-fibrotic remodeling via paracrine signaling and exosomes. Conversely, PSCs have a more structural rebuilding role and possess the ability to replace damaged cardiac cells, create new vascular structures, and allow electromechanical integration of various cell and tissue types via directed differentiation and tissue engineering. As outlined in this review, growing knowledge of the biological pathways associated with MSC and PSC early-stage repair mechanisms, alongside emerging engineering-based methodologies to enhance clinical applications, such as preconditioning, surface engineering, biomaterial-assisted delivery, differentiation engineering, maturation control, safety engineering, immune engineering, and 3D tissue assembly, has led to a paradigm shift. We now view myocardial regeneration as a systems-level regenerative process requiring coordinated regulation of vascularization, immune homeostasis, metabolism, extracellular matrix remodeling, and electrical integration. By combining the scientific approaches of stem cell biology with engineering principles, we expect this review to serve as a foundational guide for the further advancement of integrated regenerative strategies designed to provide long-lasting functional restoration of the myocardium across multiple cardiac disease states.