Mechanotransduction: The role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac function

Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA.
Pflügers Archiv - European Journal of Physiology (Impact Factor: 4.1). 07/2011; 462(1):89-104. DOI: 10.1007/s00424-011-0951-4
Source: PubMed


Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease, requiring cardiac myocytes to be mechanically durable and capable of fusing a variety of environmental signals on different time scales. During physiological growth, myocytes adaptively remodel to mechanical loads. Pathological stimuli can induce maladaptive remodeling. In both of these conditions, the cytoskeleton plays a pivotal role in both sensing mechanical stress and mediating structural remodeling and functional responses within the myocyte.

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Available from: Kevin Kit Parker, Apr 18, 2014
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    • "In turn, the cytoskeletal architecture is known to regulate gene expression [25], impulse propagation [26], excitability [27] and contraction [16] [28], demonstrating the regulatory role of cell shape on cardiac function. In vivo, adult ventricular cardiomyocytes are elongated and aligned along one axis with length/width ratios of 7:1 [17] [24]. Accordingly, restraining cell shape to a more elongated phenotype reminiscent of that of adult cardiomyocytes improves cardiomyocyte structure and function [16] [29]. "
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    ABSTRACT: Cardiomyocytes from human pluripotent stem cells (hPSC-CM) have many potential applications in disease modelling and drug target discovery but their phenotypic similarity to early fetal stages of cardiac development limits their applicability. In this study we compared contraction stresses of hPSC-CM to 2nd trimester human fetal derived cardiomyocytes (hFetal-CM) by imaging displacement of fluorescent beads by single contracting hPSC-CM, aligned by microcontact-printing on polyacrylamide gels. hPSC-CM showed distinctly lower contraction stress than cardiomyocytes isolated from hFetal-CM. To improve maturation of hPSC-CM in vitro we made use of commercial media optimized for cardiomyocyte maturation, which promoted significantly higher contraction stress in hPSC-compared with hFetal-CM. Accordingly, other features of cardiomyocyte maturation were observed, most strikingly increased upstroke velocities and action potential amplitudes, lower resting membrane potentials, improved sarcomeric organization and alterations in cardiac-specific gene expression. Performing contraction force and electrophysiology measurements on individual cardiomyocytes revealed strong correlations between an increase in contraction force and a rise of the upstroke velocity and action potential amplitude and with a decrease in the resting membrane potential. We showed that under standard differentiation conditions hPSC-CM display lower contractile force than primary hFetal-CM and identified conditions under which a commercially available culture medium could induce molecular, morphological and functional maturation of hPSC-CM in vitro. These results are an important contribution for full implementation of hPSC-CM in cardiac disease modelling and drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 05/2015; 51. DOI:10.1016/j.biomaterials.2015.01.067 · 8.56 Impact Factor
    • "Surrounding these fibers and linking them to the extracellular matrix is a cytoskeleton of protein or endomysium [1], the constituents of which have a crucial role in development and remodeling of the myocytes in response to mechanical and chemical signals [2]. The sarcoplasmic reticulum (SR) is a network of sleeve-like structures surrounding the myofibrils within a muscle fiber. "
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    ABSTRACT: The fetal circulation is an entirely transient event, not replicated at any point in later life, and functionally distinct from the pediatric and adult circulations. Understanding of the physiology of the fetal circulation is vital for accurate interpretation of hemodynamic assessments in utero, but also for management of circulatory compromise in premature infants, who begin extrauterine life before the fetal circulation has finished its maturation. This review summarizes the key classical components of circulatory physiology, as well as some of the newer concepts of physiology that have been appreciated in recent years. The immature circulation has significantly altered function in all aspects of circulatory physiology. The mechanisms and significance of these differences are also discussed, as is the impact of these alterations on the circulatory transition of infants born prematurely. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Seminars in Fetal and Neonatal Medicine 04/2015; 20(4). DOI:10.1016/j.siny.2015.04.003 · 3.03 Impact Factor
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    • "This data also indicates that presenting mature matrix stiffness to immature cells for a tissue in which the cells normally develop can also adversely affect maturation of those precursor cells. While signaling events regulating development and myofilament assembly may be fairly well described in vivo3536, the specific contributions of dynamic matrix stiffness remain uncertain but could be teased out using the matrices described here. "
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    ABSTRACT: Cells secrete and assemble extracellular matrix throughout development, giving rise to time-dependent, tissue-specific stiffness. Mimicking myocardial matrix stiffening, i.e. ~10-fold increase over 1 week, with a hydrogel system enhances myofibrillar organization of embryonic cardiomyocytes compared to static hydrogels, and thus we sought to identify specific mechanosensitive proteins involved. Expression and/or phosphorylation state of 309 unique protein kinases were examined in embryonic cardiomyocytes plated on either dynamically stiffening or static mature myocardial stiffness hydrogels. Gene ontology analysis of these kinases identified cardiogenic pathways that exhibited time-dependent up-regulation on dynamic versus static matrices, including PI3K/AKT and p38 MAPK, while GSK3β, a known antagonist of cardiomyocyte maturation, was down-regulated. Additionally, inhibiting GSK3β on static matrices improved spontaneous contraction and myofibril organization, while inhibiting agonist AKT on dynamic matrices reduced myofibril organization and spontaneous contraction, confirming its role in mechanically-driven maturation. Together, these data indicate that mechanically-driven maturation is at least partially achieved via active mechanosensing at focal adhesions, affecting expression and phosphorylation of a variety of protein kinases important to cardiomyogenesis.
    Scientific Reports 09/2014; 4:6425. DOI:10.1038/srep06425 · 5.58 Impact Factor
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