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Matrix microarchitecture and myosin II determine adhesion in 3D matrices.

ABSTRACT: Reports of adhesions in cells growing in 3D vary widely-from nonexistent to very large and elongated-and are often in apparent conflict, due largely to our minimal understanding of the underlying mechanisms that determine 3D cell phenotype. We address this problem directly by systematically identifying mechanisms that determine adhesion in 3D matrices and, from our observations, develop principles widely applicable across 2D and 3D substrates.We demonstrate that nonmuscle myosin II activity guides adhesion phenotype in 3D as it does in 2D; however, in contrast to 2D, decreasing bulk matrix stiffness does not necessarily inhibit the formation of elongated adhesions. Even in soft 3D matrices, cells can form large adhesions in areas with appropriate local matrix fiber alignment. We further show that fiber orientation, apart from influencing local stiffness, modulates the available adhesive area and thereby determines adhesion size.Thus adhesion in 3D is determined by both myosin activity and the immediate microenvironment of each adhesion, as defined by the local matrix architecture. Important parameters include not only the resistance of the fiber to pulling (i.e., stiffness) but also the orientation and diameter of the fiber itself. These principles not only clarify conflicts in the literature and point to adhesion modulating factors other than stiffness, but also have important implications for tissue engineering and studies of tumor cell invasion.

SUBMITTER: Kubow KE

PROVIDER: S-EPMC3773288 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Matrix microarchitecture and myosin II determine adhesion in 3D matrices.

Kubow Kristopher E KE Conrad Sarah K SK Horwitz A Rick AR

Current biology : CB 20130808 17

<h4>Background</h4>Reports of adhesions in cells growing in 3D vary widely-from nonexistent to very large and elongated-and are often in apparent conflict, due largely to our minimal understanding of the underlying mechanisms that determine 3D cell phenotype. We address this problem directly by systematically identifying mechanisms that determine adhesion in 3D matrices and, from our observations, develop principles widely applicable across 2D and 3D substrates.<h4>Results</h4>We demonstrate tha ...[more]

PMID: 23932405

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Project description:Cell motility under physiological and pathological conditions including malignant progression of cancer and subsequent metastasis are founded on environmental confinements. During the last two decades, three-dimensional cell migration has been studied mostly by utilizing biomimetic extracellular matrix models. In the majority of these studies, the in vitro collagen scaffolds are usually assumed to be homogenous, as they consist commonly of one specific type of collagen, such as collagen type I, isolated from one species. These collagen matrices should resemble in vivo extracellular matrix scaffolds physiologically, however, mechanical phenotype and functional reliability have been addressed poorly due to certain limitations based on the assumption of homogeneity. How local variations of extracellular matrix structure impact matrix mechanics and cell migration is largely unknown. Here, we hypothesize that local inhomogeneities alter cell movement due to alterations in matrix mechanics, as they frequently occur in in vivo tissue scaffolds and were even changed in diseased tissues. To analyze the effect of structural inhomogeneities on cell migration, we used a mixture of rat tail and bovine dermal collagen type I as well as pure rat and pure bovine collagens at four different concentrations to assess three-dimensional scaffold inhomogeneities. Collagen type I from rat self-assembled to elongated fibrils, whereas bovine collagen tended to build node-shaped inhomogeneous scaffolds. We have shown that the elastic modulus determined with atomic force microscopy in combination with pore size analysis using confocal laser scanning microscopy revealed distinct inhomogeneities within collagen matrices. We hypothesized that elastic modulus and pore size govern cancer cell invasion in three-dimensional collagen matrices. In fact, invasiveness of three breast cancer cell types is altered due to matrix-type and concentration indicating that these two factors are crucial for cellular invasiveness. Our findings revealed that local matrix scaffold inhomogeneity is another crucial parameter to explain differences in cell migration, which not solely depended on pore size and stiffness of the collagen matrices. With these three distinct biophysical parameters, characterizing structure and mechanics of the studied collagen matrices, we were able to explain differences in the invasion behavior of the studied cancer cell lines in dependence of the used collagen model.

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Matrix microarchitecture and myosin II determine adhesion in 3D matrices.

Publications

Matrix microarchitecture and myosin II determine adhesion in 3D matrices.

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