Effects of Substrate Mechanics on Contractility of Cardiomyocytes Generated from Human Pluripotent Stem Cells

Hazeltine, Laurie B.; Simmons, Chelsey S.; Salick, Max R.; Lian, Xiaojun; Badur, Mehmet G.; Han, Wenqing; Delgado, Stephanie M.; Wakatsuki, Toshiyuki; Crone, Wendy C.; Pruitt, Beth L.; Palecek, Sean P.

doi:10.1155/2012/508294

Cited by 150 publications

(150 citation statements)

References 40 publications

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“…2C. The failure of the CE model on soft gels is expected from cultured CM experiments (7,8,22). Remarkably, we find agreement between the SE model with cell-on-gel measurements, demonstrating that we can deduce this single CM behavior as a function of E quantitatively from collective behavior in tissue.…”

Section: Se Model Is Consistent With Cell-on-gel Measurements With Nosupporting

confidence: 65%

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Mechanical signaling coordinates the embryonic heartbeat

Chiou

Rocks

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, β-glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts-consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats. mechanotransduction | excitable media | cardiac development | heartbeat | reaction-diffusion

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Section: Se Model Is Consistent With Cell-on-gel Measurements With Nosupporting

confidence: 65%

“…1A, Inset). This behavior is observed for embryonic and neonatal CMs cultured on hydrogels (5,7,8,22) and has been studied theoretically (23).…”

Section: Physical Model Of Cardiac Mechanical Signalingmentioning

confidence: 81%

Mechanical signaling coordinates the embryonic heartbeat

Chiou

Rocks

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies found that 10-kPa substrates yield useful cultures of immature primary neonatal murine CMs with physiological shape (21,23). Increasing substrate stiffness without controlling cell shape increases the force output of neonatal murine CMs (25) and unpatterned hPSC-CMs (24). We found that variations in stiffness affect the mechanical output of engineered hPSC-CMs by changing myofibril function.…”

Section: Discussionmentioning

confidence: 53%

“…Along with cell shape, substrate stiffness affects the cytoskeleton (23) and mechanical phenotypes of cells (24,25) and may regulate the mechanical output of engineered hPSC-CMs. Generally, tension along the cell membrane increases with the aspect ratio of adherent cells (26).…”

Section: Resultsmentioning

confidence: 99%

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Ribeiro

Ang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Single cardiomyocytes contain myofibrils that harbor the sarcomerebased contractile machinery of the myocardium. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs) have potential as an in vitro model of heart activity. However, their fetallike misalignment of myofibrils limits their usefulness for modeling contractile activity. We analyzed the effects of cell shape and substrate stiffness on the shortening and movement of labeled sarcomeres and the translation of sarcomere activity to mechanical output (contractility) in live engineered hPSC-CMs. Single hPSC-CMs were cultured on polyacrylamide substrates of physiological stiffness (10 kPa), and Matrigel micropatterns were used to generate physiological shapes (2,000-μm 2 rectangles with length:width aspect ratios of 5:1-7:1) and a mature alignment of myofibrils. Translation of sarcomere shortening to mechanical output was highest in 7:1 hPSC-CMs. Increased substrate stiffness and applied overstretch induced myofibril defects in 7:1 hPSC-CMs and decreased mechanical output. Inhibitors of nonmuscle myosin activity repressed the assembly of myofibrils, showing that subcellular tension drives the improved contractile activity in these engineered hPSC-CMs. Other factors associated with improved contractility were axially directed calcium flow, systematic mitochondrial distribution, more mature electrophysiology, and evidence of transverse-tubule formation. These findings support the potential of these engineered hPSC-CMs as powerful models for studying myocardial contractility at the cellular level.contractility | sarcomeres | cardiomyocyte | stem cell | single cell

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“…In particular, both the morphology and beating of embryonic heart muscle cells or cardiomyocytes have been observed to depend sensitively on the rigidity of the substrate on which they are cultured [4][5][6][7][8] .…”

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confidence: 99%

Substrate stiffness-modulated registry phase correlations in cardiomyocytes map structural order to coherent beating

et al. 2015

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Recent experiments show that both striation, an indication of the structural registry in muscle fibres, as well as the contractile strains produced by beating cardiac muscle cells can be optimized by substrate stiffness. Here we show theoretically how the substrate rigidity dependence of the registry data can be mapped onto that of the strain measurements. We express the elasticity-mediated structural registry as a phase-order parameter using a statistical physics approach that takes the noise and disorder inherent in biological systems into account. By assuming that structurally registered myofibrils also tend to beat in phase, we explain the observed dependence of both striation and strain measurements of cardiomyocytes on substrate stiffness in a unified manner. The agreement of our ideas with experiment suggests that the correlated beating of heart cells may be limited by the structural order of the myofibrils, which in turn is regulated by their elastic environment.

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Effects of Substrate Mechanics on Contractility of Cardiomyocytes Generated from Human Pluripotent Stem Cells

Cited by 150 publications

References 40 publications

Mechanical signaling coordinates the embryonic heartbeat

Mechanical signaling coordinates the embryonic heartbeat

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Substrate stiffness-modulated registry phase correlations in cardiomyocytes map structural order to coherent beating

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