Inelastic behaviour of collagen networks in cell–matrix interactions and mechanosensation

Mohammadi, Hamid; Arora, Pamma D.; Simmons, Craig A.; Janmey, Paul A.; McCulloch, Christopher A.

doi:10.1098/rsif.2014.1074

Cited by 62 publications

(51 citation statements)

References 55 publications

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“…The results from this study support the growing body of experimental and theoretical work that indicates that the fibrous nature of biological gels is responsible for enhanced long-distance cell mechanosensing compared to nonfibrous gels [14][15][16][17]30,[46][47][48]. Several of these theoretical studies have found that the mechanosensing length scale of a cell increases when fibers are accounted for in the model [14,30,46,48].…”

Section: Discussionsupporting

confidence: 74%

Fiber Network Models Predict Enhanced Cell Mechanosensing on Fibrous Gels

Aghvami

Billiar

Sander

2016

Journal of Biomechanical Engineering

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The propagation of mechanical signals through nonlinear fibrous tissues is much more extensive than through continuous synthetic hydrogels. Results from recent studies indicate that increased mechanical propagation arises from the fibrous nature of the material rather than the strain-stiffening property. The relative importance of different parameters of the fibrous network structure to this propagation, however, remains unclear. In this work, we directly compared the mechanical response of substrates of varying thickness subjected to a constant cell traction force using either a nonfibrous strain-stiffening continuum-based model or a volume-averaged fiber network model consisting of two different types of fiber network structures: one with low fiber connectivity (growth networks) and one with high fiber connectivity (Delaunay networks). The growth network fiber models predicted a greater propagation of substrate displacements through the model and a greater sensitivity to gel thickness compared to the more connected Delaunay networks and the nonlinear continuum model. Detailed analysis of the results indicates that rotational freedom of the fibers in a network with low fiber connectivity is critically important for enhanced, long-range mechanosensing. Our findings demonstrate the utility of multiscale models in predicting cells mechanosensing on fibrous gels, and they provide a more complete understanding of how cell traction forces propagate through fibrous tissues, which has implications for the design of engineered tissues and the stem cell niche.

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Section: Discussionsupporting

confidence: 74%

Fiber Network Models Predict Enhanced Cell Mechanosensing on Fibrous Gels

Aghvami

Billiar

Sander

2016

Journal of Biomechanical Engineering

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“…Tissue contraction depends on the combination of cell density and type, 21 matrix type and associated physical properties, 42–44 and physical boundary conditions. 22,43 Culture surface coating with glutaraldehyde, polyethylenimine, or poly-L-lysine may be applied to improve construct adherence and minimize contraction. 45,46 …”

Section: Resultsmentioning

confidence: 99%

In Vitro Multitissue Interface Model Supports Rapid Vasculogenesis and Mechanistic Study of Vascularization across Tissue Compartments

Buno

Weibel

Thiede

et al. 2016

ACS Appl. Mater. Interfaces

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A significant challenge facing tissue engineers is the design and development of complex multitissue systems, including vascularized tissue–tissue interfaces. While conventional in vitro models focus on either vasculogenesis (de novo formation of blood vessels) or angiogenesis (vessels sprouting from existing vessels or endothelial monolayers), successful therapeutic vascularization strategies will likely rely on coordinated integration of both processes. To address this challenge, we developed a novel in vitro multitissue interface model in which human endothelial colony forming cell (ECFC)-encapsulated tissue spheres are embedded within a surrounding tissue microenvironment. This highly reproducible approach exploits biphilic surfaces (nanostructured surfaces with distinct superhydrophobic and hydrophilic regions) to (i) support tissue compartments with user-specified matrix composition and physical properties as well as cell type and density and (ii) introduce boundary conditions that prevent the cell-mediated tissue contraction routinely observed with conventional three-dimensional monodispersion cultures. This multitissue interface model was applied to test the hypothesis that independent control of cell–extracellular matrix (ECM) and cell–cell interactions would affect vascularization within the tissue sphere as well as across the tissue–tissue interface. We found that high-cell-density tissue spheres containing 5 × 106 ECFCs/mL exhibit rapid and robust vasculogenesis, forming highly interconnected, stable (as indicated by type IV collagen deposition) vessel networks within only 3 days. Addition of adipose-derived stromal cells (ASCs) in the surrounding tissue further enhanced vasculogenesis within the sphere as well as angiogenic vessel elongation across the tissue–tissue boundary, with both effects being dependent on the ASC density. Overall, results show that the ECFC density and ECFC–ASC crosstalk, in terms of paracrine and mechanophysical signaling, are critical determinants of vascularization within a given tissue compartment and across tissue interfaces. This new in vitro multitissue interface model and the associated mechanistic insights it yields provide guiding principles for the design and optimization of multitissue vascularization strategies for research and clinical applications.

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“…Notably, the design of the grid-supported collagen model and the low cell plating density used for laterally supported and underlying supported gels, enabled study of cell extension formation and collagen remodeling of individual cells, which is in contrast to the more complex mechanics that are measured with higher plating densities and the combinatorial effects of multiple interacting cells. The inferences derived from this model indicate that collagen compaction precedes cell extension formation, which relates to the irreversible inelastic deformation properties of collagen gels described earlier [73,74]. PAK1 phosphorylation has been used as an indicator of PAK1 kinase activity [49] and effector function in actin assembly [29].…”

Section: Discussionmentioning

confidence: 98%

PAK1 is involved in sensing the orientation of collagen stiffness gradients in mouse fibroblasts

Pinto

Mohammadi

Lee

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Migrating cells sense variations of stiffness in connective tissue matrices but how cells detect and respond to stiffness orientation is not defined. We examined cell extension formation on collagen with underlying support (vertical stiffness gradient) or on collagen laterally supported by nylon (lateral stiffness gradient). At 6 h after plating, cells plated on laterally-supported collagen exhibited >2-fold more abundant and ~2-fold longer cell extensions than cells plated on collagen with underlying support. We examined whether p21-activated kinase 1 (PAK1) influences extension formation that is dependent on the orientation of support. At 6 h after plating on collagen with underlying support, wild-type cell extensions were 40% shorter than PAK1 knockdown cells. In contrast, on laterally-supported collagen, wild-type cell extensions were 2-fold longer than PAK1 knockdown cells. In cells plated on laterally-supported collagen, there were ~2-fold reductions of collagen fiber alignment and compaction in PAK1 knockdown cells compared with wild-type cells. PAK1 knockdown did not affect collagen fiber alignment or compaction by cells plated on collagen with underlying support. Wild-type cells with lateral support of collagen exhibited 3-fold increases of phospho-myosin staining at 6h, which was 2-fold lower in PAK1 knockdown cells. In contrast, cells on collagen with underlying support showed no increase of phospho-myosin staining at any times. PAK1 knockdown did not affect α2 or β1 integrin expression or function. We conclude that PAK1 is involved in the ability of cells to sense the orientation of stiffness in collagen substrates and generate contractile forces that affect cell extension formation.

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Inelastic behaviour of collagen networks in cell–matrix interactions and mechanosensation

Cited by 62 publications

References 55 publications

Fiber Network Models Predict Enhanced Cell Mechanosensing on Fibrous Gels

Fiber Network Models Predict Enhanced Cell Mechanosensing on Fibrous Gels

In Vitro Multitissue Interface Model Supports Rapid Vasculogenesis and Mechanistic Study of Vascularization across Tissue Compartments

PAK1 is involved in sensing the orientation of collagen stiffness gradients in mouse fibroblasts

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