Cooperative coupling of cell-matrix and cell-cell adhesions in cardiac muscle
Cooperative coupling of cell-matrix and cell-cell adhesions in cardiac muscle
复制标题
DOI：
10.1073/pnas.1203007109
复制
发表时间：
2012-06-19
影响因子：
11.1
通讯作者：
Parker, Kevin Kit
中科院分区：
文献类型：
--
作者：
McCain, Megan L.;Lee, Hyungsuk;Parker, Kevin Kit
心肌细胞之间的粘附对于心脏作为机电合胞体发挥功能是必不可少的。虽然细胞-基质和细胞-细胞粘附在发育和疾病过程中重组，但这些亚细胞结构之间的层次合作知之甚少。我们推断，在心脏发育过程中，局部粘连在肌原纤维发生和闰盘组装过程中机械地稳定细胞和组织。随着椎间盘的成熟，我们推测当收缩期应力在细胞间传递时，粘连灶会解体。最后，我们假设心脏微环境的病理性重塑诱导闰盘的过度机械负荷，导致连接附近稳定性局灶性粘连的组装。为了测试我们的模型，我们设计了由两个心室肌细胞组成的mu组织，它们位于可调弹性的可变形基底上，以测量肌原纤维、局灶性粘连和闰盘作为合作集合体的动态组织和功能重塑。成熟的mu组织增加了收缩力，同时通过分解细胞-细胞界面处的粘着斑并形成传递收缩负荷的成熟闰盘而发展成机电合胞体。我们发现，模拟纤维化的微环境工程导致邻近细胞-细胞界面的粘着斑形成，这表明闰盘需要机械加固。在这些病理微环境中，mu组织表现出适应不良重塑的进一步证据，包括较低的工作效率，较长的收缩周期持续时间，以及细胞骨架组织和力产生之间的关系减弱。这些结果表明，心脏中细胞-基质和细胞-细胞粘附之间的合作平衡是由发育期间建立的结构和功能层次结构指导的，并在疾病期间被破坏。
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.