Cell contraction induces long-ranged stress stiffening in the extracellular matrix

Han, Yu; Ronceray, Pierre; Xu, Guoqiang; Malandrino, Andrea; Kamm, Roger D.; Lenz, Martin; Broedersz, Chase P.; Guo, Ming

doi:10.1073/pnas.1722619115

Cited by 263 publications

(238 citation statements)

References 57 publications

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“…al. (34) indeed demonstrated that stiffness becomes anisotropic near contracting cells, with a higher extent of stiffening in the radial relative to the angular direction. Moreover, in our simulations, radially aligned fibers are stretched, whereas angularly aligned fibers are typically compressed (Fig.…”

Section: Strain-induced Elastic Anisotropy: Effects Of Fiber Alignmenmentioning

confidence: 85%

Elastic Anisotropy Governs the Range of Cell-Induced Displacements

Goren

Koren

et al. 2020

Biophysical Journal

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SignificanceTissues are made up of cells and an extracellular matrix (ECM), a cross-linked network of stiff biopolymers. Cells actively alter the ECM structure and mechanics by applying contractile forces, which allow them to sense other distant cells and regulate many tissue functions. We study theoretically the decay of cell-induced displacements in fibrous networks, while quantifying the changes in the elastic properties of the cell's local environment. We demonstrate that cell contraction induce an anisotropic elastic state, i.e., unequal principal elastic moduli, in the ECM which dictates the slow decay of displacements. These observations suggest a new mechanical mechanism through which cells can mechanically communicate over long distances, and may provide biomaterials design parameters to guide morphogenesis in tissue engineering. AbstractThe unique nonlinear mechanics of the fibrous extracellular matrix (ECM) facilitates long-range cell-cell mechanical communications that would be impossible on linear elastic substrates. Past research has described the contribution of two separated effects on the range of force transmission, including ECM elastic non-linearity and fiber alignment. However, the relation between these different effects is unclear, and how they combine to dictate force transmission range is still elusive. Here, we combine discrete fiber simulations with continuum modeling to study the decay of displacements induced by a contractile cell in fibrous networks. We demonstrate that fiber non-linearity and fiber reorientation both contribute to the Page 2 of 32 strain-induced anisotropy of the elastic moduli of the cell's local environment. This elastic anisotropy is a "lumped" parameter that governs the slow decay of the displacements, and it depends on the magnitude of applied strain, either an external tension or an internal contraction as a model of the cell. Furthermore, we show that accounting for artificially-prescribed elastic anisotropy dictates the displacement decay induced by a contracting cell. Our findings unify previous single effects into a mechanical theory that explains force transmission in fibrous networks. This work provides important insights into biological processes that involve the coordinated action of distant cells mediated by the ECM, such that occur in morphogenesis, wound healing, angiogenesis, and cancer metastasis. It may also provide design parameters for biomaterials to control force transmission between cells, as a way to guide morphogenesis in tissue engineering.In addition, we find in Fig. 3C that the data points of 2 / 1 for all types of fibers can be approximately fitted by a master curve if plotted versus the normalized strain, / crit . Here crit is the critical strain, a characteristic parameter of the network, in which 2 / 1 becomes smaller than 0.9, and the strain-induced elastic anisotropy is significant. The normalized strain, / crit , similar to the normalized cell contraction, / crit in cell contraction networks, is another "emergent" dimensionless p...

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Section: Strain-induced Elastic Anisotropy: Effects Of Fiber Alignmenmentioning

confidence: 85%

Elastic Anisotropy Governs the Range of Cell-Induced Displacements

Goren

Koren

et al. 2020

Biophysical Journal

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“…1 C-E). Furthermore, this highly stretchable helix scaffold exhibits a strong nonlinear elasticity in the form of strain stiffening, which is widely observed in biopolymer networks and is thought to be of importance for tissue mechanical functions (36,46). The deformation process includes original separation of the adjacent coils and gradual unwinding of the coils until the fiber is free of it.…”

Section: Resultsmentioning

confidence: 99%

Helical nanofiber yarn enabling highly stretchable engineered microtissue

Guo

Hao

et al. 2019

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

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Development of microtissues that possess mechanical properties mimicking those of native stretchable tissues, such as muscle and tendon, is in high demand for tissue engineering and regenerative medicine. However, regardless of the significant advances in synthetic biomaterials, it remains challenging to fabricate living microtissue with high stretchability because application of large strains to microtissues can damage the cells by rupturing their structures. Inspired by the hierarchical helical structure of native fibrous tissues and its behavior of nonaffine deformation, we develop a highly stretchable and tough microtissue fiber made up of a hierarchical helix yarn scaffold, scaling from nanometers to millimeters, that can overcome this limitation. This microtissue can be stretched up to 15 times its initial length and has a toughness of 57 GJ m−3. More importantly, cells grown on this scaffold maintain high viability, even under severe cyclic strains (up to 600%) that can be attributed to the nonaffine deformation under large strains, mimicking native biopolymer scaffolds. Furthermore, as proof of principle, we demonstrate that the nanotopography of the helical nanofiber yarn is able to induce cytoskeletal alignment and nuclear elongation, which promote myogenic differentiation of mesenchymal stem cells by triggering nuclear translocation of transcriptional coactivator with PDZ-binding motif (TAZ). The highly stretchable microtissues we develop here will facilitate a variety of tissue engineering applications and the development of engineered living systems.

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“…This reference state does not account for irreversible, inelastic deformations of the matrix, which may occur due to ECM remodeling or deposition. In future work, complementary measurements using optical tweezers 20,23 or direct imaging of fibers 18 could also be incorporated to address how multicellular clusters are affected by changes in the local stiffness of the surrounding matrix. Our classification of multicellular cluster mechanophenotype directly accounts for local spatial heterogeneity in the local 3D matrix deformation patterns.…”

Section: Discussionmentioning

confidence: 99%

“…Early TFM studies measured cell-cell and cell-matrix interactions of multicellular epithelial clusters on planar 2D substrates [8][9][10][11][12][13] . More recently, TFM has been extended to 3D hydrogels, but has primarily focused on individual cells [14][15][16][17][18][19][20][21][22][23][24] . Notably, epithelial cell lines exhibit more isotropic, spatially uniform tractions, while mesenchymal cell lines exhibit highly anisotropic tractions localized at the leading and trailing edge 14-16, 18, 20, 22, 23 .…”

Section: Introductionmentioning

confidence: 99%

Mechanophenotyping of 3D Multicellular Clusters using Displacement Arrays of Rendered Tractions

Leggett

Patel

Valentin

et al. 2019

Preprint

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Epithelial tissues mechanically deform the surrounding extracellular matrix during embryonic development, wound repair, and tumor invasion. Ex vivo measurements of such multicellular tractions within three-dimensional (3D) biomaterials could elucidate collective dissemination during disease progression, and enable preclinical testing of targeted anti-migration therapies. However, past 3D traction measurements have been low throughput due to the challenges of imaging and analyzing information-rich 3D material deformations. Here, we demonstrate a method to profile multicellular clusters in a 96-well plate format based on spatially heterogeneous contractile, protrusive, and circumferential tractions. As a case study, we profile multicellular clusters across varying states of the epithelial-mesenchymal transition, revealing a successive loss of protrusive and circumferential tractions, as well as the formation of localized contractile tractions with elongated cluster morphologies. These cluster phenotypes were biochemically perturbed using drugs, biasing towards traction signatures of different epithelial or mesenchymal states. This higher-throughput analysis is promising to systematically interrogate and perturb aberrant mechanobiology, which could be utilized with human patient samples to guide personalized therapies.

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Cell contraction induces long-ranged stress stiffening in the extracellular matrix

Cited by 263 publications

References 57 publications

Elastic Anisotropy Governs the Range of Cell-Induced Displacements

Elastic Anisotropy Governs the Range of Cell-Induced Displacements

Helical nanofiber yarn enabling highly stretchable engineered microtissue

Mechanophenotyping of 3D Multicellular Clusters using Displacement Arrays of Rendered Tractions

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