Mechanotransduction and extracellular matrix homeostasis

Humphrey, Jay D.; Dufresne, Eric R.; Schwartz, Martin A.

doi:10.1038/nrm3896

Cited by 1,695 publications

(1,491 citation statements)

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“…Recent studies highlight the importance of physical forces within cells and tissues in the regulation of key biological processes including growth, differentiation, development, and cancer (Discher et al ., 2005; Assoian & Klein, 2008; Butcher et al ., 2009; Janmey & Miller, 2011; Janmey et al ., 2013; Humphrey et al ., 2014; Iskratsch et al ., 2014). The impact of mechanobiology on cutaneous biology and in particular skin aging is relatively unexplored.…”

Section: Discussionmentioning

confidence: 99%

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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SummaryThe structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.

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Section: Discussionmentioning

confidence: 99%

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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“…In contrast, pulsatile shear stress (PS) in the straight parts of the arteries is atheroprotective (1). At the cellular and molecular levels, disturbed flow pattern increases, while PS inhibits, the inflammatory response in ECs, including the expression of intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin 1β (IL-1β) (2). We found that integrins in ECs are shear stress-sensitive (3).…”

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confidence: 86%

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Sun

et al. 2016

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

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Local flow patterns determine the uneven distribution of atherosclerotic lesions. Membrane lipid rafts and integrins are crucial for shear stress-regulated endothelial function. In this study, we investigate the role of lipid rafts and integrin α5 in regulating the inflammatory response in endothelial cells (ECs) under atheroprone versus atheroprotective flow. Lipid raft proteins were isolated from ECs exposed to oscillatory shear stress (OS) or pulsatile shear stress, and then analyzed by quantitative proteomics. Among 396 proteins redistributed in lipid rafts, integrin α5 was the most significantly elevated in lipid rafts under OS. In addition, OS increased the level of activated integrin α5 in lipid rafts through the regulation of membrane cholesterol and fluidity. Disruption of F-actin-based cytoskeleton and knockdown of caveolin-1 prevented the OS-induced integrin α5 translocation and activation. In vivo, integrin α5 activation and EC dysfunction were observed in the atheroprone areas of low-density lipoprotein receptor-deficient (Ldlr −/− ) mice, and knockdown of integrin α5 markedly attenuated EC dysfunction in partially ligated carotid arteries. Consistent with these findings, mice with haploinsufficency of integrin α5 exhibited a reduction of atherosclerotic lesions in the regions under atheroprone flow. The present study has revealed an integrin-and membrane lipid raft-dependent mechanotransduction mechanism by which atheroprone flow causes endothelial dysfunction.integrin | lipid rafts | shear stress | proteomics | endothelial dysfunction S hear stress imposed on vascular endothelial cells (ECs) influences vascular phenotype and function. Atherosclerosis preferentially develops at branches and curvatures in the arterial tree where flow is disturbed. In contrast, pulsatile shear stress (PS) in the straight parts of the arteries is atheroprotective (1). At the cellular and molecular levels, disturbed flow pattern increases, while PS inhibits, the inflammatory response in ECs, including the expression of intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin 1β (IL-1β) (2). We found that integrins in ECs are shear stress-sensitive (3). Many subsequent studies demonstrated that integrin activation is essential for transmitting mechanical stimuli to intracellular biochemical pathways (4-6). Additionally, mounting evidence indicates that lipid raft microdomains, membrane receptors, cytoskeletal proteins, and extracellular matrices are linked to integrin activation in the context of mechanotransduction (7-11). However, the key mechanism underlying the differential effects of atheroprone versus atheroprotective flows in activating integrins that in turn induces inflammatory response in ECs remains to be elucidated.Lipid rafts are membrane microdomains that are enriched in cholesterol, sphingolipids, and a variety of signaling molecules, which function as cellular signaling platforms. These microdomains are more ordered and tightly packed than the surrounding membran...

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“…proliferation) and the surrounding matrix by growth (increase in tissue mass) and remodeling (changes in tissue structure). It is believed that these processes occur to maintain a cellmediated mechanical homeostasis 1,2 . Yet, the mechanisms through which this mechanical homeostasis is maintained remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

A Bioreactor to Identify the Driving Mechanical Stimuli of Tissue Growth and Remodeling

Kelle

Oomen

Bulsink

et al. 2017

Tissue Engineering Part C: Methods

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Mechanotransduction and extracellular matrix homeostasis

Cited by 1,695 publications

References 154 publications

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

A Bioreactor to Identify the Driving Mechanical Stimuli of Tissue Growth and Remodeling

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