Mechanical Properties of the Extracellular Matrix Influence Fibronectin Fibril Assembly in Vitro

Halliday, Nancy; Tomasek, James J.

doi:10.1006/excr.1995.1069

Cited by 193 publications

(143 citation statements)

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“…3). These findings reinforce earlier reports where inhibitors of Fn fibrillogenesis did not affect fibroblast behavior in 3D collagen gels (Halliday and Tomasek 1995). Similar analyses of Fn matrix assembly in wild-type and Fn knockout embryos indicate that distinct differences exist between embryonic fibroblast and endothelial cell behavior in vivo and in vitro (George et al 1993;Deroanne et al 1996;Hocking et al 2000;Sottile et al 2000;Deroanne et al 2001;Francis et al 2002).…”

Section: Discussionsupporting

confidence: 87%

Fibronectin fibrillogenesis regulates three-dimensional neovessel formation

Zhou¹,

Rowe²,

Hiraoka³

et al. 2008

Genes Dev.

182

156

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During vasculogenesis and angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. While 3D-embedded endothelial cells establish adhesive interactions with surrounding ligands to optimally respond to soluble or matrix-bound agonists, the manner in which a randomly ordered ECM with diverse physico-mechanical properties is remodeled to support blood vessel formation has remained undefined. Herein, we demonstrate that endothelial cells initiate neovascularization by unfolding soluble fibronectin (Fn) and depositing a pericellular network of fibrils that serve to support cytoskeletal organization, actomyosin-dependent tension, and the viscoelastic properties of the embedded cells in a 3D-specific fashion. These results advance a new model wherein Fn polymerization serves as a structural scaffolding that displays adhesive ligands on a mechanically ideal substratum for promoting neovessel development.[Keywords: Actomyosin; angiogenesis; endothelial cells; extracellular matrix; fibronectin] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionsupporting

confidence: 87%

Fibronectin fibrillogenesis regulates three-dimensional neovessel formation

Zhou¹,

Rowe²,

Hiraoka³

et al. 2008

Genes Dev.

182

156

View full text Add to dashboard Cite

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“…Cells encapsulated in attached versus floating collagen gels also modulate expression of cytoskeletal and ECM proteins, illustrating the importance of mechanics in 3D settings (39)(40)(41). Here, by constraining microtissues, using flexible cantilevers, we simultaneously varied boundary and matrix stiffness with quantitative precision, and demonstrated that in 3D matrices, cellular contractility is regulated by overall stiffness whereas protein expression correlates with mechanical stress.…”

Section: Discussionmentioning

confidence: 85%

Microfabricated tissue gauges to measure and manipulate forces from 3D microtissues

Legant

Pathak

Yang

et al. 2009

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

375

442

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Physical forces generated by cells drive morphologic changes during development and can feedback to regulate cellular phenotypes. Because these phenomena typically occur within a 3-dimensional (3D) matrix in vivo, we used microelectromechanical systems (MEMS) technology to generate arrays of microtissues consisting of cells encapsulated within 3D micropatterned matrices. Microcantilevers were used to simultaneously constrain the remodeling of a collagen gel and to report forces generated during this process. By concurrently measuring forces and observing matrix remodeling at cellular length scales, we report an initial correlation and later decoupling between cellular contractile forces and changes in tissue morphology. Independently varying the mechanical stiffness of the cantilevers and collagen matrix revealed that cellular forces increased with boundary or matrix rigidity whereas levels of cytoskeletal and extracellular matrix (ECM) proteins correlated with levels of mechanical stress. By mapping these relationships between cellular and matrix mechanics, cellular forces, and protein expression onto a bio-chemo-mechanical model of microtissue contractility, we demonstrate how intratissue gradients of mechanical stress can emerge from collective cellular contractility and finally, how such gradients can be used to engineer protein composition and organization within a 3D tissue. Together, these findings highlight a complex and dynamic relationship between cellular forces, ECM remodeling, and cellular phenotype and describe a system to study and apply this relationship within engineered 3D microtissues.biomechanics ͉ cell mechanics ͉ collagen ͉ morphogenesis ͉ PDMS

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“…This suggests that Smad3 regulation of MMP secretion and/or activation may require integrin/collagen interactions. Changes in integrin/extracellular matrix interactions can alter adhesion, cell shape, and protease expression, secretion, and activity in multiple cell types (34)(35)(36)(37)(38). In addition, mechanotransduction by Smad3 has been shown in a mouse model for incisional wound closure (39).…”

Section: Smad3 Mediates An Emt In Ovarian Cancer Cells Mol Cancer Resmentioning

confidence: 99%

Transforming Growth Factor-β1, Transforming Growth Factor-β2, and Transforming Growth Factor-β3 Enhance Ovarian Cancer Metastatic Potential by Inducing a Smad3-Dependent Epithelial-to-Mesenchymal Transition

Kubba²,

et al. 2008

Molecular Cancer Research

110

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Transforming growth factor-B (TGF-B) is thought to play a role in the pathobiological progression of ovarian cancer because this peptide hormone is overexpressed in cancer tissue, plasma, and peritoneal fluid. In the current study, we investigated the role of the TGF-B/ Smad3 pathway in ovarian cancer metastasis by regulation of an epithelial-to-mesenchymal transition. When cancer cells were cultured on plastic, TGF-B1, TGF-B2, and TGF-B3 induced pro -matrix metalloproteinase (MMP) secretion, loss of cell-cell junctions, down-regulation of E-cadherin, up-regulation of N-cadherin, and acquisition of a fibroblastoid phenotype, consistent with an epithelial-tomesenchymal transition. Furthermore, Smad3 small interfering RNA transfection inhibited TGF-B -mediated changes to a fibroblastic morphology, but not MMP secretion. When cancer cells were cultured on a three-dimensional collagen matrix, TGF-B1, TGF-B2, and TGF-B3 stimulated both pro-MMP and active MMP secretion and invasion. Smad3 small interfering RNA transfection of cells cultured on a collagen matrix abrogated TGF-B -stimulated invasion and MMP secretion. Analysis of Smad3 nuclear expression in microarrays of serous benign tumors, borderline tumors, and cystadenocarcinoma revealed that Smad3 expression could be used to distinguish benign and borderline tumors from carcinoma (P = 0.006). Higher Smad3 expression also correlated with poor survival (P = 0.031). Furthermore, a direct relationship exists between Smad3 nuclear expression and expression of the mesenchymal marker N-cadherin in cancer patients (P = 0.0057). Collectively, these results implicate an important role for the TGF-B/Smad3 pathway in mediating ovarian oncogenesis by enhancing metastatic potential. (Mol Cancer Res 2008;6(5):695 -705)

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Mechanical Properties of the Extracellular Matrix Influence Fibronectin Fibril Assembly in Vitro

Cited by 193 publications

References 0 publications

Fibronectin fibrillogenesis regulates three-dimensional neovessel formation

Fibronectin fibrillogenesis regulates three-dimensional neovessel formation

Microfabricated tissue gauges to measure and manipulate forces from 3D microtissues

Transforming Growth Factor-β1, Transforming Growth Factor-β2, and Transforming Growth Factor-β3 Enhance Ovarian Cancer Metastatic Potential by Inducing a Smad3-Dependent Epithelial-to-Mesenchymal Transition

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