Tissue Cells Feel and Respond to the Stiffness of Their Substrate

Discher, Dennis E.; Janmey, Paul A.; Wang, Yu Li

doi:10.1126/science.1116995

Cited by 5,416 publications

(4,820 citation statements)

References 82 publications

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142

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“…These stiffness values are in the region of many soft tissues and compare well to previously published peptide hydrogel systems, including aromatic peptides4, 17 and peptide–amphiphile hydrogels 27, 28. The ability to tune the G′ value across a large range holds great promise for applications in tissue engineering, given that the behavior of cells has been found to be heavily influenced by the mechanical properties of their surrounding environment 29, 30…”

supporting

confidence: 79%

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

2018

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Oligopeptide‐based supramolecular hydrogels hold promise in a range of applications. The gelation of these systems is hard to control, with minor alterations in the peptide sequence significantly influencing the self‐assembly process. We explored three pentapeptide sequences with different charge distributions and discovered that they formed robust, pH‐responsive hydrogels. By altering the concentration and charge distribution of the peptide sequence, the stiffness of the hydrogels could be tuned across two orders of magnitude (2–200 kPa). Also, through reassembly of the β‐sheet interactions the hydrogels could self‐heal and they demonstrated shear‐thin behavior. Using spectroscopic and cryo‐imaging techniques, we investigated the relationship between peptide sequence and molecular structure, and how these influence the mechanical properties of the hydrogel. These pentapeptide hydrogels with tunable morphology and mechanical properties have promise in tissue engineering, injectable delivery vectors, and 3D printing applications.

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supporting

confidence: 79%

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

2018

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“…One possibility is that tissue/matrix stiffness directly affects the cytoskeleton and thereby cell behaviour (Discher et al , 2005; Halder et al , 2012), as described in the concept of cellular “tensegrity” (Ingber & Jamieson, 1985). Our work demonstrated that the presence of laminin α5 in endothelial basement membrane correlates with increased endothelial cell cortical stiffness in vivo and in vitro , which suggests changes in cortical actin arrangement may also mechanically affect junctional proteins (Engl et al , 2014; Sauteur et al , 2014).…”

Section: Discussionmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

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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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Tissue Cells Feel and Respond to the Stiffness of Their Substrate

Cited by 5,416 publications

References 82 publications

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

Endothelial basement membrane laminin 511 is essential for shear stress response

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

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