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Cooperative Coupling of Cell-Matrix and Cell–Cell Adhesions in Cardiac Muscle

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Cooperative Coupling of Cell-Matrix and Cell–Cell Adhesions in Cardiac Muscle Cooperative coupling of cell-matrix and cell–cell adhesions in cardiac muscle Megan L. McCaina, Hyungsuk Leea,1, Yvonne Aratyn-Schausa, André G. Kléberb, and Kevin Kit Parkera,2 aDisease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; and bDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved May 1, 2012 (received for review February 21, 2012) Adhesion between cardiac myocytes is essential for the heart to serve as cues for remodeling adhesions and assembling tissues. In function as an electromechanical syncytium. Although cell-matrix vitro studies have demonstrated that cytoskeletal tension (27) and and cell–cell adhesions reorganize during development and dis- exogenous cyclic strain (28, 29) promote cell–cell adhesion and ease, the hierarchical cooperation between these subcellular struc- tissue assembly in many cell types. Culturing noncardiac cells tures is poorly understood. We reasoned that, during cardiac on stiff substrates tips the balance of adhesion in favor of focal development, focal adhesions mechanically stabilize cells and tis- adhesions and away from cell–cell adhesions (30–32), suggesting sues during myofibrillogenesis and intercalated disc assembly. As that mechanical forces can modulate the assembly or disassembly the intercalated disc matures, we postulated that focal adhesions of tissues. Many cardiomyopathies are characterized by increased disassemble as systolic stresses are transmitted intercellularly. fibrosis and tissue stiffening (33, 34), suggesting that cardiac myo- Finally, we hypothesized that pathological remodeling of cardiac cytes might be similarly sensitive to tissue compliance and favor microenvironments induces excessive mechanical loading of inter- focal adhesion formation over cell–cell junction formation in a calated discs, leading to assembly of stabilizing focal adhesions fibrotic microenvironment. adjacent to the junction. To test our model, we engineered μtissues We hypothesized that focal adhesions mechanically stabilize composed of two ventricular myocytes on deformable substrates myocytes during tissue assembly, when myofibrils are contractile of tunable elasticity to measure the dynamic organization and but the intercalated disc is not yet fully assembled. We postulated functional remodeling of myofibrils, focal adhesions, and interca- that focal adhesions disassemble as intercalated discs mature lated discs as cooperative ensembles. Maturing μtissues increased such that systolic forces are transmitted intercellularly. Further- systolic force while simultaneously developing into an electrome- more, we reasoned that stiff microenvironments potentiate exces- chanical syncytium by disassembling focal adhesions at the cell–cell sive intrinsic loading that destabilizes the intercalated disc and interface and forming mature intercalated discs that transmitted induces focal adhesion formation near the cell–cell junction. the systolic load. We found that engineering the microenvironment We modeled developing, healthy, and diseased cardiac tissue to mimic fibrosis resulted in focal adhesion formation adjacent to by engineering μtissues composed of two neonatal rat ventricular the cell–cell interface, suggesting that the intercalated disc re- myocytes on deformable substrates of tunable elasticity. To char- quired mechanical reinforcement. In these pathological microenvir- acterize progressive stages of tissue assembly, we cultured μtis- onments, μtissues exhibited further evidence of maladaptive remo- sues on physiological substrates and measured structural and deling, including lower work efficiency, longer contraction cycle functional outputs over time. μtissues gradually increased systolic duration, and weakened relationships between cytoskeletal orga- force generation, disassembled focal adhesions near the cell–cell nization and force generation. These results suggest that the coop- interface, and formed intercalated discs to transmit the systolic erative balance between cell-matrix and cell–cell adhesions in the load. Tomimic diseased myocardium, we cultured μtissues on stiff heart is guided by an architectural and functional hierarchy estab- substrates and observed further increases in force generation, lished during development and disrupted during disease. maladaptive functional remodeling, and focal adhesion forma- tion adjacent to the cell–cell interface. These data suggest that adherens junctions ∣ sarcomere ∣ mechanotransduction ∣ extracellular regulation of cell-matrix and cell–cell adhesions during cardiac matrix development is guided by an intrinsic hierarchy that is altered in disease due to mechanical remodeling of the microenvir- n the adult heart, healthy ventricular tissue is characterized onment. Iby spatial segregation of cell-matrix adhesions to transverse myocyte borders (1) and cell–cell adhesions to longitudinal myo- Results cyte borders (2). Many cardiomyopathies are characterized by ECM Regulates Cooperative Intra- and Intercellular Assembly. We hy- BIOPHYSICS AND lateralization of cell–cell adhesions (3–5), increased expression pothesized that focal adhesion attachments to the ECM are of cell-matrix adhesions (6, 7), and arrhythmogenesis (8), suggest- important in development for directing migration and myofibril- COMPUTATIONAL BIOLOGY ing that spatially organized adhesion is essential for effective logenesis and stabilizing myocytes as they become contractile. eletromechanical coupling (9). Although in vivo studies have However, we suspected that focal adhesions adjacent to the cell– shown that localization of cell-matrix and cell–cell adhesions is cell junction disassemble once the intercalated disc is capable of developmentally regulated (10–13), the factors that regulate their transmitting systolic loads intercellularly. To test this model, we assembly and disassembly are not well understood. Cell-matrix adhesions are especially important during organo- Author contributions: M.L.M., H.L., Y.A.-S., A.G.K., and K.K.P. designed research; M.L.M. genesis, anchoring developing cells and tissues to the extracellu- performed research; M.L.M., H.L., and Y.A.-S. contributed new reagents/analytic tools; lar matrix (ECM) (14) and directing cell migration (15–17). As M.L.M., H.L., and Y.A.-S. analyzed data; and M.L.M. and K.K.P. wrote the paper. development progresses, cell-matrix adhesions must selectively The authors declare no conflict of interest. disassemble so that cell–cell adhesions can form (18). In the This article is a PNAS Direct Submission. heart, this exchange of adhesion sites occurs while myocytes are 1Present address: School of Mechanical Engineering, Yonsei University, Seoul 120-749, contractile (19, 20), indicating that myofibrils, cell–cell, and cell- Korea. matrix adhesions must cooperatively remodel without compro- 2To whom correspondence should be addressed. E-mail: [email protected]. – – mising cardiac output. Because cell-matrix (21 24) and cell cell This article contains supporting information online at www.pnas.org/lookup/suppl/ adhesions (25, 26) are mechanosensitive, mechanical forces likely doi:10.1073/pnas.1203007109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1203007109 PNAS ∣ June 19, 2012 ∣ vol. 109 ∣ no. 25 ∣ 9881–9886 Downloaded by guest on October 2, 2021 engineered rectangular μtissues consisting of two neonatal rat Although focal adhesions are critical early in tissue assembly, ventricular myocytes on micropatterned fibronectin (FN) we reasoned that focal adhesions near the cell–cell interface dis- islands and monitored them over time. Eight hours after seeding, assemble as adjacent intercalated discs establish intercellular spreading myocytes typically protruded along a lateral edge of the mechanical continuity. To investigate this, we immunostained island, independent of whether one (Fig. 1A) or two myocytes for paxillin to monitor differences in focal adhesion localization between μtissues cultured on micropatterned polyacrylamide gels (Fig. 1B) adhered to the island. After 12 h, μtissues filled the – with physiological stiffness (13 kPa) (35) for 1 d (Day 1) and 4 d island and striated myofibrils and sigmoid-like cell cell interfaces (Day 4) to represent immature and mature tissues, respectively. C D were observable (Fig. 1 and ). In contrast, myocytes on sub- At Day 1 (Fig. 1E), paxillin signal, although relatively diffuse, was strates coated with uniform FN extended randomly oriented pro- detected in plaques at the longitudinal ends of the μtissue, colo- trusions before forming confluent, isotropic monolayers (Fig. S1 calized with terminating myofibrils. Paxillin plaques were also A–C). Cell–cell junctions were relatively linear (Fig. S1D) and detected near the cell–cell interface, suggestive of focal adhesion perpendicular to myofibrils, characteristic of junctions in vivo formation. At Day 4 (Fig. 1F), paxillin signal was localized to the (2). These results indicate that cell-ECM interactions guide cell longitudinal ends of the μtissue in larger and more distinct pla- spreading and myofibrillogenesis early in tissue assembly, influ- ques. Near the cell–cell interface, paxillin signal appeared rela- – encing cell–cell junction formation by regulating myocyte shape. tively weak, suggesting that focal adhesions near the cell cell interface disassembled
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