Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, with the limited regenerative capacity of the adult myocardium posing a significant therapeutic challenge. Mechanobiology has emerged as a critical discipline for advancing cardiac regenerative medicine by elucidating how mechanical forces regulate cardiac development, homeostasis, disease progression, and, in particular, regeneration. This narrative review provides a comprehensive overview of mechanobiology, specifically in the context of cardiac regeneration. The cardiac mechanical microenvironment, governed by extracellular matrix composition, passive stiffness mediated by collagen and titin, and dynamic mechanical loading, profoundly influences cardiomyocyte behavior, stem cell differentiation toward cardiac lineages, and functional integration of regenerative grafts. Mechanotransduction pathways, mediated through integrins, focal adhesion complexes, mechanosensitive ion channels (TRPV4, TRPC1, TRPC6, KATP, CFTR), cytoskeletal remodeling, and YAP/TAZ signaling, convert mechanical stimuli into biochemical signals that regulate gene expression, cardiomyocyte maturation, proliferation, and targeted cardiac remodeling for repair. Substrate stiffness, topography, and viscoelasticity have been demonstrated to direct stem cell differentiation into cardiomyocytes, promote their structural and functional maturation, alignment, and contractile performance, key requirements for effective cell therapy and engineered cardiac tissues. Biomaterial-based strategies (employing polydimethylsiloxane, polyacrylamide hydrogels, and composite scaffolds) and advanced in vitro models (ranging from two-dimensional microcontact printing to three-dimensional engineered heart tissues) are highlighted for their ability to recapitulate the native cardiac mechanical environment and enhance regenerative outcomes. Computational mechanobiology approaches, including finite element analysis and multi-scale simulations, provide quantitative frameworks for optimizing scaffold design and predicting tissue regeneration under complex loading conditions. Despite significant advances, challenges such as the immature phenotype of stem cell-derived cardiomyocytes, incomplete replication of native myocardial mechanics by current biomaterials, and gaps in mechanotransduction understanding persist. Emerging technologies, including organ-on-a-chip platforms, four-dimensional bioprinting, smart dynamically tunable biomaterials, multi-omics integration, and artificial intelligence-driven modeling, offer transformative potential to translate mechanobiological principles into clinically effective cardiac regenerative therapies. This review underscores that mechanobiology constitutes an indispensable pillar for developing next-generation strategies in cardiac regeneration.
Pisheh et al. (Wed,) studied this question.