Collagen processing, crosslinking, and fibril bundle assembly in matrix produced by fibroblasts in long-term cultures supplemented with ascorbic acid

Grinnell, Frederick; Fukamizu, Hidekazu; Pawelek, Pamela; Nakagawa, S

doi:10.1016/0014-4827(89)90105-5

Cited by 112 publications

(63 citation statements)

References 17 publications

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“…20, we propose a mechanism in which there exists an orientation field coupled to nearby particles and that this field can, in turn, affect the orientation of those particles. For fibroblasts, this idea is supported by the fact that cells secrete materials for ECM, such as collagen (16,17). Furthermore, as fibroblasts move, they contract and align ECM fibers depending on their direction of motion (18,19).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we further test models in which nonlocal interactions between fibroblasts are introduced. Biologically, these models are motivated by the observations (16)(17)(18)(19) that fibroblasts are able to deposit and reorganize fibril materials around them. Using this model, we investigated whether coupling between cells and their mechanical environment can recapitulate patterns of fibroblasts both in vitro and in vivo.…”

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confidence: 99%

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On the mechanism of long-range orientational order of fibroblasts

Balagam

et al. 2017

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

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Long-range alignment ordering of fibroblasts have been observed in the vicinity of cancerous tumors and can be recapitulated with in vitro experiments. However, the mechanisms driving their ordering are not understood. Here, we show that local collisiondriven nematic alignment interactions among fibroblasts are insufficient to explain observed long-range alignment. One possibility is that there exists another orientation field coevolving with the cells and reinforcing their alignment. We propose that this field reflects the mechanical cross-talk between the fibroblasts and the underlying fibrous material on which they move. We show that this long-range interaction can give rise to high nematic order and to the observed patterning of the cancer microenvironment.alignment | fibroblasts | long-range order | extracellular matrix | collagen fibers F ibroblasts are spindle-shaped cells that are highly motile and are involved in many critical biological processes, such as wound healing (1, 2). Recently, their major role in shaping the local microenvironment around a growing tumor was shown in numerous studies (3-5). As a result, fibroblasts can affect the ability of cancer cells to metastasize (6-8) and conversely, the ability of the immune system to find and attack those cells (9).An isolated fibroblast moves back and forth on coverslips for over 60 h without significant change of the direction of its major axis (10). Typically, those fibroblasts are in a spindle shape with an aspect ratio from two to five. Apart from steric constraints, fibroblasts barely interact with each other (10). Curiously, imaging of tumor microenvironments often indicates longrange ordering of fibroblasts. This order often takes the form of circumferential alignment of the cells in a region surrounding the cancer cells (11,12). The mechanisms that lead to this ordering are not well-understood.Notably, a similar ordering can be observed for underlying collagen fibers (6, 13). Collagen fibers are the main structural component in the extracellular space of various normal connective tissues and play a significant role in local cancer cell invasion and in metastasis (14). Aligned fibers perpendicular to the boundary cancer cell clusters facilitate local invasions of cancer cells, and conversely, aligned fibers parallel to the tumor boundary may restrict the migration of cancer cells. Furthermore, the circumferential collagen fiber structure has been hypothesized to be responsible for the observed separation between immune and cancer cells (13). Specifically, ex vivo assays indicate that the migration of tumor-killing CD8 + T cells is reduced where dense collagen fibers form conduit-like structures (15). Therefore, understanding the mechanism of the pattern formation of fibroblasts and collagen fibers in the cancer microenvironment is important to strike a balance between constraining cancer cell from invasion and enabling the infiltration of cancer-killing immune cells.In vivo experimental observation of this pattern formation dynamically is techn...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

On the mechanism of long-range orientational order of fibroblasts

Balagam

et al. 2017

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

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“…Such matrices include Matrigel (produced by EHS tumors, (Kleinman et al, 1986)), polymerized collagen (Grinnell et al, 2006;Grinnell et al, 1989), and other synthetic media (e.g., (Hwang et al, 2006)). Clearly, these matrices can regulate the growth of tumor cells in many ways, affecting their proliferation, morphology, survival signaling, invasive potential and response to chemotherapeutic agents (Griffith and Swartz, 2006).…”

Section: Introductionmentioning

confidence: 99%

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

et al. 2008

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Recent studies have emphasized the importance of cellular microenvironment in modulating cell growth and signaling. In vitro, collagen matrices, Matrigel, and other synthetic support systems have been used to simulate in vivo microenvironments, and epithelial cells grown in these matrices manifest significant differences in proliferation, differentiation, response to drugs, and other parameters. However, these substrates do not closely resemble the mesenchymal microenvironment that is typically associated with advanced carcinomas in vivo, which is produced to a large extent by fibroblasts. In this study, we have evaluated the ability of a fibroblast-derived three-dimensional matrix to regulate the growth of a panel of 11 human tumor epithelial cell lines. Although proliferative and morphological responses to three-dimensional cues segregated independently, general responsiveness to the matrix correlated with the ability of matrix to influence drug responses. Fibroblast-derived three-dimensional matrix increased β1-integrin-dependent survival of a subset of human cancer cell lines during taxol treatment, while it sensitized or minimally influenced survival of other cells. β1-integrin-dependent changes in cell resistance to taxol did not correlate with degree of modulation of FAK and Akt, implying additional signaling factors are involved. Based on these results, we propose these matrices potentially have value as in vitro drug screening platforms.

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“…Tractional forces generated by cells play critical roles in both embryogenesis (5,6) and wound healing (7,8). Fibroblasts grown on type I collagen gels extensively modify the collagen gels (7)(8)(9)(10)(11)(12)(13)(14)(15). This contraction of collagen gels composed of reconstituted collagen fibrils by fibroblasts in vitro is used by many Manuscript received August 16, 1991; revised manuscript received August 5, 1992; accepted August 10, 1992.…”

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confidence: 99%

Contraction of collagen gels by intestinal epithelial cells depends on microfilament function

Olson

1993

Digest Dis Sci

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Collagen processing, crosslinking, and fibril bundle assembly in matrix produced by fibroblasts in long-term cultures supplemented with ascorbic acid

Cited by 112 publications

References 17 publications

On the mechanism of long-range orientational order of fibroblasts

On the mechanism of long-range orientational order of fibroblasts

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

Contraction of collagen gels by intestinal epithelial cells depends on microfilament function

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