Toward single cell traction microscopy within 3D collagen matrices

Hall, Matthew S.; Long, Rong; Feng, Xinzeng; Huang, Yu‐Ling; Hui, Chung‐Yuen; Wu, Mingming

doi:10.1016/j.yexcr.2013.06.009

Cited by 88 publications

(84 citation statements)

References 132 publications

(166 reference statements)

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“…and coworkers (24). We first measure collagen matrix deformation using a 3D particle tracking microscopy (37,38). Breast cancer cells are embedded within a collagen matrix covalently bonded to fluorescent marker beads (Fig.…”

Section: Measuring Cell Force By Tracking Matrix Deformation and Applmentioning

confidence: 99%

Fibrous nonlinear elasticity enables positive mechanical feedback between cells and ECMs

Hall

Alisafaei

Ban

et al. 2016

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

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In native states, animal cells of many types are supported by a fibrous network that forms the main structural component of the ECM. Mechanical interactions between cells and the 3D ECM critically regulate cell function, including growth and migration. However, the physical mechanism that governs the cell interaction with fibrous 3D ECM is still not known. In this article, we present single-cell traction force measurements using breast tumor cells embedded within 3D collagen matrices. We recreate the breast tumor mechanical environment by controlling the microstructure and density of type I collagen matrices. Our results reveal a positive mechanical feedback loop: cells pulling on collagen locally align and stiffen the matrix, and stiffer matrices, in return, promote greater cell force generation and a stiffer cell body. Furthermore, cell force transmission distance increases with the degree of strain-induced fiber alignment and stiffening of the collagen matrices. These findings highlight the importance of the nonlinear elasticity of fibrous matrices in regulating cell-ECM interactions within a 3D context, and the cell force regulation principle that we uncover may contribute to the rapid mechanical tissue stiffening occurring in many diseases, including cancer and fibrosis.cell traction force | 3D cell traction force microscopy | fibrous nonlinear elasticity | cell-ECM interaction | collagen A nimal cells of most cell types, including breast tumor cells, are supported structurally by a fibrous ECM within a 3D context (1, 2). Cells adhere to the fibers via the linkages between integrin receptors on the membrane surface and the adhesion molecules within the ECM. To migrate, cells pull/push along the fibers or squeeze through the pore structure of the network (3). The tensional balance between the cell and the ECM critically regulates many physiological and pathological processes, including immune response, tissue formation, and tumor progression (4-7). In the breast tumor, stiffening of the mechanical environment disrupts force balance between epithelial cells and the ECM, promoting a malignant phenotype (5, 8). Tumors stiffen as cells deposit more collagen than they digest (9-11), increasingly express cross-linking enzymes (8, 12), and exert traction forces to reorganize the ECM (13).The main structural component of the ECM is a network of cross-linked protein fibers. The fiber network aligns, stiffens, and sometimes, undergoes permanent changes when subjected to strain (14, 15). These adaptive mechanical properties of the fiber network provide cells entry points to modify their local microenvironment (16-18) and as such, perform physiologically realistic functions (1,3,(19)(20)(21)(22)(23). It has been reported that the nonlinear elasticity of fibrous matrices enables cells to transmit forces over distances of hundreds of micrometers, facilitating long-range communication between individual cells (24-26) and between tumor spheroids (27). Recent work has shown that individual cells are capable of stiffening the...

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Section: Measuring Cell Force By Tracking Matrix Deformation and Applmentioning

confidence: 99%

Fibrous nonlinear elasticity enables positive mechanical feedback between cells and ECMs

Hall

Alisafaei

Ban

et al. 2016

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

Self Cite

310

282

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“…In this work, the bead concentration resulted in a mean particle spacing of approximately 12.5 µm. By comparison, recent work in TFM makes use of mean particle spacings in the range of 1.5 µm to 25 µm, though high sampling frequency methods tend to keep within the 1.5 -3 µm regime [25].…”

Section: Sample Preparation For Effective Cross-correlation-based Dismentioning

confidence: 99%

“…One area of interest is that of collective cellular behavior, where 2D TFM studies have revealed several collective cellular behaviors including wave patterns in cell migration fronts [18], spacefilling behaviors [19], tendencies to minimize intercellular shear stresses [20], and jamming transitions [5,21]. Recent work has led to the development of TFM in 3D cell culture, with confocal microscopy taking the lead as the modality of choice to enable imaging of 3D samples and deformations [15,17,[22][23][24][25][26]. It remains an open area of research how the collective cell behaviors observed in 2D settings will translate within 3D environments.…”

Section: Introductionmentioning

confidence: 99%

Measurement of dynamic cell-induced 3D displacement fields in vitro for traction force optical coherence microscopy

Mulligan

Bordeleau

Reinhart‐King

et al. 2017

Biomed. Opt. Express

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Traction force microscopy (TFM) is a method used to study the forces exerted by cells as they sense and interact with their environment. Cell forces play a role in processes that take place over a wide range of spatiotemporal scales, and so it is desirable that TFM makes use of imaging modalities that can effectively capture the dynamics associated with these processes. To date, confocal microscopy has been the imaging modality of choice to perform TFM in 3D settings, although multiple factors limit its spatiotemporal coverage. We propose traction force optical coherence microscopy (TF-OCM) as a novel technique that may offer enhanced spatial coverage and temporal sampling compared to current methods used for volumetric TFM studies. Reconstructed volumetric OCM data sets were used to compute time-lapse extracellular matrix deformations resulting from cell forces in 3D culture. These matrix deformations revealed clear differences that can be attributed to the dynamic forces exerted by normal versus contractility-inhibited NIH-3T3 fibroblasts embedded within 3D Matrigel matrices. Our results are the first step toward the realization of 3D TF-OCM, and they highlight the potential use of OCM as a platform for advancing cell mechanics research. 7(4), 265-275 (2006).

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“…This is a direct consequence of the scalingκ ∼ ϕ ∝ (a/ l 0 ) 2 , which remains invariant to changes in fibril thickness for a given total protein concentration. The structure of collagen networks, including fibril thickness, mesh size, homogeneity, and presumably connectivity, depends in detail on concentration and polymerization conditions in nontrivial ways [37,38]. However, under the basic assumptions mentioned above,κ remains a constant.…”

Section: Relationship Between Model and Experimental Parametersmentioning

confidence: 99%

Strain-driven criticality underlies nonlinear mechanics of fibrous networks

et al. 2016

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Networks with only central force interactions are floppy when their average connectivity is below an isostatic threshold. Although such networks are mechanically unstable, they can become rigid when strained. It was recently shown that the transition from floppy to rigid states as a function of simple shear strain is continuous, with hallmark signatures of criticality [Sharma et al., Nature Phys. 12, 584 (2016)]. The nonlinear mechanical response of collagen networks was shown to be quantitatively described within the framework of such mechanical critical phenomenon. Here, we provide a more quantitative characterization of critical behavior in subisostatic networks. Using finite-size scaling we demonstrate the divergence of strain fluctuations in the network at well-defined critical strain. We show that the characteristic strain corresponding to the onset of strain stiffening is distinct from but related to this critical strain in a way that depends on critical exponents. We confirm this prediction experimentally for collagen networks. Moreover, we find that the apparent critical exponents are largely independent of the spatial dimensionality. With subisostaticity as the only required condition, strain-driven criticality is expected to be a general feature of biologically relevant fibrous networks.

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Toward single cell traction microscopy within 3D collagen matrices

Cited by 88 publications

References 132 publications

Fibrous nonlinear elasticity enables positive mechanical feedback between cells and ECMs

Fibrous nonlinear elasticity enables positive mechanical feedback between cells and ECMs

Measurement of dynamic cell-induced 3D displacement fields in vitro for traction force optical coherence microscopy

Strain-driven criticality underlies nonlinear mechanics of fibrous networks

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