Mechanobiology in cardiac regenerative medicine: from fundamental principles to therapeutic applications.
6 affiliations
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
- 2Shiraz Institute for Stem Cell & Regenerative Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- 3Department of Biology, Payam Noor University (PNU), Shiraz, Iran.
- 4Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake, UT84112, USA.
- 5Department of Tissue Engineering and Regenerative Medicine, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- 6Center for Nanotechnology in Drug Delivery, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. [email protected].
Abstract
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, K_ATP, 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.
Related
- Mechanobiology in Osteoarthritis: From Crosstalk of Mechanosensitive Signaling Pathways to the Intervention Mechanisms and Therapeutic Potential of Exercise.
- Chronic Inflammation, Fibrotic Remodeling, and Regenerative Failure in Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Opportunities
- The clinical applications of platelet-rich plasma and platelet-rich fibrin combined with photobiomodulation in regenerative dentistry: A literature review.
- Regenerative Medicine in the Management of Musculoskeletal Pain: Mechanisms, Clinical Applications, and Future Directions.
- Lung Ultrasound in Children: Principles, Techniques, and Clinical Applications.
BibTeX
@article{pisheh2026mechanobiology,
title = {{Mechanobiology in cardiac regenerative medicine: from fundamental principles to therapeutic applications.}},
author = {Hossein Rayat Pisheh and Ali Rayat Pisheh and Mona Latifi and Farnaz Sani and Seyed Saeid Masoomkhah and Ahmad Darvishi},
journal = {Stem cell research \& therapy},
year = {2026},
month = aug,
doi = {10.1186/s13287-026-05231-x},
url = {https://europepmc.org/article/MED/42972466},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Mechanobiology in cardiac regenerative medicine: from fundamental principles to therapeutic applications.
AU - Hossein Rayat Pisheh
AU - Ali Rayat Pisheh
AU - Mona Latifi
AU - Farnaz Sani
AU - Seyed Saeid Masoomkhah
AU - Ahmad Darvishi
PY - 2026
DA - 2026/08/05
JO - Stem cell research & therapy
DO - 10.1186/s13287-026-05231-x
UR - https://europepmc.org/article/MED/42972466
AB - 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, K_ATP, 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.
SN - 1757-6512
ER -