Biased cell migration of fibroblasts exhibiting contact guidance in oriented collagen gels

We search in this paper for context-specific modes of three-dimensional (3D) cell migration using imaging for phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and active Rac1 and Cdc42 in primary fibroblasts migrating within different 3D environments. In 3D collagen, PIP3 and active Rac1 and Cdc42 were targeted to the leading edge, consistent with lamellipodia-based migration. In contrast, elongated cells migrating inside dermal explants and the cell-derived matrix (CDM) formed blunt, cylindrical protrusions, termed lobopodia, and Rac1, Cdc42, and PIP3 signaling was nonpolarized. Reducing RhoA, Rho-associated protein kinase (ROCK), or myosin II activity switched the cells to lamellipodia-based 3D migration. These modes of 3D migration were regulated by matrix physical properties. Specifically, experimentally modifying the elasticity of the CDM or collagen gels established that nonlinear elasticity supported lamellipodia-based migration, whereas linear elasticity switched cells to lobopodia-based migration. Thus, the relative polarization of intracellular signaling identifies two distinct modes of 3D cell migration governed intrinsically by RhoA, ROCK, and myosin II and extrinsically by the elastic behavior of the 3D extracellular matrix.

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The use of three-dimensional collagen gels for the study of tumour cell invasionin vitro: Experimental parameters influencing cell migration into the gel matrix

International Journal of Cancer ◽

10.1002/ijc.2910290110 ◽

1982 ◽

Vol 29 (1) ◽

pp. 57-62 ◽

Cited By ~ 65

Author(s):

Seth L. Schor ◽

Ana M. Schor ◽

Brian Winn ◽

Graham Rushton

Keyword(s):

Cell Migration ◽

Tumour Cell ◽

Three Dimensional ◽

Collagen Gels ◽

Experimental Parameters

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An Anisotropic Biphasic Theory of Tissue-Equivalent Mechanics: The Interplay Among Cell Traction, Fibrillar Network Deformation, Fibril Alignment, and Cell Contact Guidance

Journal of Biomechanical Engineering ◽

10.1115/1.2796072 ◽

1997 ◽

Vol 119 (2) ◽

pp. 137-145 ◽

Cited By ~ 245

Author(s):

V. H. Barocas ◽

R. T. Tranquillo

Keyword(s):

Contact Guidance ◽

Deformation Tensor ◽

Cell Contact ◽

Cell Alignment ◽

Collagen Gels ◽

Cell Orientation ◽

Collagen Network ◽

Orientation Tensor ◽

Tissue Equivalents ◽

Cell Traction

We present a general mathematical theory for the mechanical interplay in tissue-equivalents (cell-populated collagen gels): Cell traction leads to compaction of the fibrillar collagen network, which for certain conditions such as a mechanical constraint or inhomogeneous cell distribution, can result in inhomogeneous compaction and consequently fibril alignment, leading to cell contact guidance, which affects the subsequent compaction. The theory accounts for the intrinsically biphasic nature of collagen gel, which is comprised of collagen network and interstitial solution. The theory also accounts for fibril alignment due to inhomogeneous network deformation, that is, anisotropic strain, and for cell alignment in response to fibril alignment. Cell alignment results in anisotropic migration and traction, as modeled by a cell orientation tensor that is a function of a fiber orientation tensor, which is defined by the network deformation tensor. Models for a variety of tissue-equivalents are shown to predict qualitatively the alignment that arises due to inhomogeneous compaction driven by cell traction.

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Differential response of fetal and adult fibroblasts to cytokines: cell migration and hyaluronan synthesis

Development ◽

10.1242/dev.124.8.1593 ◽

1997 ◽

Vol 124 (8) ◽

pp. 1593-1600 ◽

Cited By ~ 2

Author(s):

I. Ellis ◽

J. Banyard ◽

S.L. Schor

Keyword(s):

Cell Migration ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Elevated Level ◽

Fibroblast Growth ◽

Collagen Gels ◽

Fibroblast Migration ◽

Fetal Fibroblasts ◽

Adult Fibroblasts ◽

Adult Cells

Previous studies have indicated that fetal skin fibroblasts display an elevated level of migratory activity compared to adult cells and that this may result from inherent differences in the production of hyaluronan (HA) by these cells. Data presented in this communication indicate that the elevated level of fetal fibroblast migration into 3D-collagen gels and HA synthesis by these cells were not affected by epidermal growth factor (EGF), platelet-derived growth factor (PDGF), acidic fibroblast growth factor (aFGF) or basic fibroblast growth factor (bFGF). In contrast, both cell migration and HA synthesis by fetal fibroblasts were inhibited by transforming growth factor-betal (TGF-beta1). Adult fibroblasts responded to these cytokines in a distinct fashion: i.e. cell migration and HA synthesis were stimulated by EGF, PDGF, aFGF and bFGF, but remained unaffected by TGF-beta1. Gel-filtration chromatography revealed that these effects of cytokines on HA synthesis were predominantly confined to the production of high molecular mass (>106 kDa) species. Co-exposure of cells to both cytokines and Streptomyces hyaluronidase revealed that (1) the elevated migration of control fetal fibroblasts was inhibited by hyaluronidase, (2) this inhibition was partially restored by co-exposure to EGF, PDGF, aFGF and bFGF, but remained unaffected by TGF-beta1, (3) the migration of control adult fibroblasts was unaffected by hyaluronidase and partially stimulated by EGF, aFGF and bFGF (when compared to the effects of these cytokines on cells cultured in the absence of hyaluronidase) and (4) neither PDGF nor TGF-beta1 affected the migration of hyaluronidase-treated adult cells. Linear regression analysis revealed a significant correlation between cell migration and HA synthesis by both fetal and adult fibroblasts in the presence and absence of cytokines (r2=0.9277, P<0.0001), with the exception of adult fibroblasts exposed to PDGF. Taken together, these findings suggest that (1) the migration of fetal and adult fibroblasts is differentially modulated by exogenous cytokines and (2) with the possible exception of the effects of PDGF on adult fibroblasts, cytokine-induced modulation of cell migration appears to utilise both HA-dependent and HA-independent pathways.

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