Dance Band on the
            <i>Titanic</i>

Sussman, Mark A.; McCulloch, Andrew D.; Borg, Thomas K.

doi:10.1161/01.res.0000041680.43270.f8

Cited by 95 publications

(55 citation statements)

References 188 publications

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“…Cardiac fibroblasts are scattered amongst the myofibers, secreting components of the extracellular matrix (ECM) and transmitting mechanical force by the receptor mediated connections to the ECM [35,36]. One of the challenges of cardiac tissue engineering is reproducing the "in-vivo-like" orientation and elongation of the cells in an engineered cardiac patch.…”

Section: Discussionmentioning

confidence: 99%

Interactive effects of surface topography and pulsatile electrical field stimulation on orientation and elongation of fibroblasts and cardiomyocytes

Au¹,

Cheng²,

Chowdhury³

et al. 2007

Biomaterials

177

166

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In contractile tissues such as myocardium, functional properties are directly related to the cellular orientation and elongation. Thus, tissue engineering of functional cardiac patches critically depends on our understanding of the interaction between multiple guidance cues such as topographical, adhesive or electrical. The main objective of this study was to determine the interactive effects of contact guidance and electrical field stimulation on elongation and orientation of fibroblasts and cardiomyocytes, major cell populations of the myocardium. Polyvinyl surfaces were abraded using lapping paper with grain size 1 to 80μm, resulting in V-shaped abrasions with the average abrasion peak-to-peak width in the range from 3 to 13μm, and the average depth in the range from 140nm to 700nm (AFM). The surfaces with abrasions 13μm wide and 700nm deep, exhibited the strongest effect on neonatal rat cardiomyocyte elongation and orientation as well as statistically significant effect on orientation of fibroblasts, thus they were utilized for electrical field stimulation. Electrical field stimulation was performed using a regime of relevance for heart tissue in vivo as well as for cardiac tissue engineering. Stimulation (square pulses, 1ms duration, 1Hz, 2.3V/cm or 4.6V/cm) was initiated 24hr after cell seeding and maintained for additional 72hr. The cover slips were positioned between the carbon rod electrodes so that the abrasions were either parallel or perpendicular to the field lines. Non-abraded surfaces were utilized as controls. Field stimulation did not affect cell viability (live/dead staining). The presence of a well developed contractile apparatus in neonatal rat cardiomyocytes (staining for cardiac Troponin I and actin filaments) was identified in the groups cultivated on abraded surfaces in the presence of field stimulation. Overall we observed that i) fibroblast and cardiomyocyte elongation on non-abraded surfaces was significantly enhanced by electrical field stimulation ii) electrical field stimulation promoted orientation of fibroblasts in the direction perpendicular to the field lines when the abrasions were also placed perpendicular to the field lines and iii) topographical cues were a significantly stronger determinant of cardiomyocyte orientation than the electrical field stimulation. The orientation and elongation response of cardiomyocytes was completely abolished by inhibition of actin polymerization (Cytochalasin D) and only partially by inhibition of phosphatidyl-inositol 3 kinase (PI3K) pathway (LY294002).

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Section: Discussionmentioning

confidence: 99%

Interactive effects of surface topography and pulsatile electrical field stimulation on orientation and elongation of fibroblasts and cardiomyocytes

Au¹,

Cheng²,

Chowdhury³

et al. 2007

Biomaterials

177

166

View full text Add to dashboard Cite

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“…As an example of the lessons we can learn from the study of mechanotransduction of specific cells, consider the cardiomyocyte. Mechanotransduction in the myocardium has been intensely investigated, in part because mechanical overload of the heart is highly clinically relevant (76). Most cases of heart failure are due to loss of normal myocardium (typically from a myocardial infarction), with resulting mechanical overload of the remaining viable myocardium.…”

Section: Molecular Responses Of Cells and Tissues To Mechanical Stimulimentioning

confidence: 99%

Cell mechanics and mechanotransduction: pathways, probes, and physiology

Huang

Kamm²,

Lee³

2004

American Journal of Physiology-Cell Physiology

484

367

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not only a complex biochemical environment but also a diverse biomechanical environment. How cells respond to variations in mechanical forces is critical in homeostasis and many diseases. The mechanisms by which mechanical forces lead to eventual biochemical and molecular responses remain undefined, and unraveling this mystery will undoubtedly provide new insight into strengthening bone, growing cartilage, improving cardiac contractility, and constructing tissues for artificial organs. In this article we review the physical bases underlying the mechanotransduction process, techniques used to apply controlled mechanical stresses on living cells and tissues to probe mechanotransduction, and some of the important lessons that we are learning from mechanical stimulation of cells with precisely controlled forces.cytoskeleton; micromanipulation; cell signaling ALL LIVING ORGANISMS face mechanical forces, from the fluid forces around a bacterium to the high forces in a human knee during stair climbing. The process of converting physical forces into biochemical signals and integrating these signals into the cellular responses is referred to as mechanotransduction. Although this review cannot cover all that has been discovered about mechanotransduction, we discuss the molecule-and cell-level structures that may participate in mechanotransduction, provide an overview of prominent techniques currently used for exerting mechanical stresses on cells, and conclude with an overview of the tissue-level response to mechanical signaling. FORCE TRANSDUCTION PATHWAYS AND SIGNALINGForce transmission pathways at the cellular and subcellular scales. Understanding the molecular basis for mechanotransduction requires knowledge of the magnitude and distribution of forces throughout the cell at the molecular scale. At present, we have sufficient information to measure molecular scale forces in only a very few cases. We can, however, analyze the mechanisms by which force is transmitted throughout the cell and use that as a basis for speculation about the molecular mechanisms of mechanotransduction. A variety of different methods have been used to mechanically stimulate a cell, and the cellular response is multifaceted and diverse. Similarly, there are likely to be a variety of sensing mechanisms and locations within the cell where forces can be transduced from a mechanical to a biochemical signal. Despite this apparent complexity, it is probable that cells stimulated in different ways are activated by similar mechanisms at the molecular level. To identify these commonalities, it is useful to consider how externally applied forces are transmitted into and throughout the cell, as well as the magnitudes and distribution of force corresponding to these different methods of stimulation.Both continuum and microstructural approaches have been used to determine force distributions. In the case of a continuum model, the details of the microstructure are ignored, and the forces transmitted via the individual microstructural elements are described in...

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“…Activation of several signaling pathways is a key mediator of the response to biomechanical stress. 18,19 The increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2 ( Figure 2A) and Akt ( Figure 2B) were reduced in banded PI3K␥KO mice compared with banded WT mice after 1 week of pressure overload. However, following 3 weeks of pressure overload, the degree of ERK1/2 phosphorylation was equivalent in WT and PI3K␥KO mice ( Figure 2A).…”

Section: Accelerated Development Of Ventricular Dilation and Pathologmentioning

confidence: 99%

Loss of PI3Kγ Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress

Guo

Kassiri²,

Basu³

et al. 2010

Circulation Research

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Rationale: Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K)␥, the isoform linked to G protein-coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial. Objective:To characterize molecular and cellular responses of the PI3K␥ knockout (KO) mice to biomechanical stress. Methods and Results:In response to pressure overload, PI3K␥KO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3␣. In contrast, isolated single cardiomyocytes from banded PI3K␥KO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3K␥KO mice. ␤-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3K␥ resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3K␥KO mice resulted in reduced cell adhesion. The ␤-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3K␥KO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels. Conclusions:The enhanced propensity to develop heart failure in the PI3K␥KO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/␤-catenin cell adhesion complex. ␤-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs. (Circ Res. 2010;107:1275-1289.)

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Dance Band on the Titanic

Cited by 95 publications

References 188 publications

Interactive effects of surface topography and pulsatile electrical field stimulation on orientation and elongation of fibroblasts and cardiomyocytes

Interactive effects of surface topography and pulsatile electrical field stimulation on orientation and elongation of fibroblasts and cardiomyocytes

Cell mechanics and mechanotransduction: pathways, probes, and physiology

Loss of PI3Kγ Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress

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