期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 25, 页码 9881-9886出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1203007109
关键词
adherens junctions; sarcomere; mechanotransduction; extracellular matrix
资金
- American Heart Association [0815729D]
- National Institutes of Health [1 R01 HL079126]
- Nanoscale Science and Engineering Center
- National Science Foundation [PHY-0117795, DMR-0213805]
- Harvard Materials Research Science and Engineering Center
- Wyss Institute for Biologically Inspired Engineering
- Harvard School of Engineering and Applied Sciences
- Division Of Materials Research
- Direct For Mathematical & Physical Scien [820484] Funding Source: National Science Foundation
Adhesion between cardiac myocytes is essential for the heart to function as an electromechanical syncytium. Although cell-matrix and cell-cell adhesions reorganize during development and disease, the hierarchical cooperation between these subcellular structures is poorly understood. We reasoned that, during cardiac development, focal adhesions mechanically stabilize cells and tissues during myofibrillogenesis and intercalated disc assembly. As the intercalated disc matures, we postulated that focal adhesions disassemble as systolic stresses are transmitted intercellularly. Finally, we hypothesized that pathological remodeling of cardiac microenvironments induces excessive mechanical loading of intercalated discs, leading to assembly of stabilizing focal adhesions adjacent to the junction. To test our model, we engineered mu tissues composed of two ventricular myocytes on deformable substrates of tunable elasticity to measure the dynamic organization and functional remodeling of myofibrils, focal adhesions, and intercalated discs as cooperative ensembles. Maturing mu tissues increased systolic force while simultaneously developing into an electromechanical syncytium by disassembling focal adhesions at the cell-cell interface and forming mature intercalated discs that transmitted the systolic load. We found that engineering the microenvironment to mimic fibrosis resulted in focal adhesion formation adjacent to the cell-cell interface, suggesting that the intercalated disc required mechanical reinforcement. In these pathological microenvironments, mu tissues exhibited further evidence of maladaptive remodeling, including lower work efficiency, longer contraction cycle duration, and weakened relationships between cytoskeletal organization and force generation. These results suggest that the cooperative balance between cell-matrix and cell-cell adhesions in the heart is guided by an architectural and functional hierarchy established during development and disrupted during disease.
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