Intercellular Mechanotransduction: Cellular Circuits That Coordinate Tissue Responses to Mechanical Loading

Ko, Kevin S.; McCulloch, Christopher A.

doi:10.1006/bbrc.2001.5177

Cited by 85 publications

(66 citation statements)

References 49 publications

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“…Stretch-activated ion channels in astrocytes become permeable to cations when mechanical force is applied (Bowman et al, 1992). Astrocytic mechanotransduction may also involve integrins, transmembrane proteins linking cells to ECM that, when physically deformed, activate intracellular signaling pathways regulating the activity of enzymes which may result in changes in gene expression to ultimately modify cellular behavior (Roskelley et al, 1994;Sjaastad et al, 1994;Hamill and Martinac, 2001;Ko and McCulloch, 2001;Alenghat and Ingber, 2002;Cavalcanti-Adam et al, 2005). Although the role of integrin-ECM adhesions in mechanotransduction have been well-characterized in other cell types (Katsumi et al, 2004), a link between integrin-mediated astrogliotic alterations and biomechanical inputs has not been established.…”

Section: Discussionmentioning

confidence: 99%

Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures

2007

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A mechanical insult to the brain drastically alters the microenvironment as specific cell types become reactive in an effort to sequester severely damaged tissue. Although injury-induced astrogliosis has been investigated, the relationship between well-defined biomechanical inputs and acute astrogliotic alterations are not well understood. We evaluated the effects of strain rate on cell death and astrogliosis using a three-dimensional (3-D) in vitro model of neurons and astrocytes within a bioactive matrix. At 21 days post-plating, co-cultures were deformed to 0.50 shear strain at strain rates of 1, 10, or 30 s −1 . We found that cell death and astrogliotic profiles varied differentially based on strain rate at two days post-insult. Significant cell death was observed after moderate (10 s −1 ) and high (30 s −1 ) rate deformation, but not after quasi-static (1 s −1 ) loading. The vast majority of cell death occurred in neurons, suggesting these cells are more susceptible to high rate shear strains than astrocytes for the insult parameters used here. Injury-induced astrogliosis was compared to co-cultures treated with transforming growth factor β, which induced robust astrocyte hypertrophy and increased glial fibrillary acidic protein (GFAP) and chondroitinsulfate proteoglycans (CSPGs). Quasi-static loading resulted in increased cell density and CSPG secretion. Moderate rate deformation increased cell density, GFAP reactivity, and hypertrophic process density. High rate deformation resulted in increased GFAP reactivity; however, other astrogliotic alterations were not observed at this time-point. These results demonstrate that the mode and degree of astrogliosis depend on rate of deformation, demonstrating astrogliotic augmentation at sub-lethal injury levels as well as levels inducing cell death.

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Section: Discussionmentioning

confidence: 99%

Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures

2007

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“…proteases, phosphatases, kinases) that can modify cytoskeletal organization and may result in changes in gene expression. 2,10,29,36,50,53 However, the mechanisms involved in transduction of non-physiological mechanical deformation are not fully understood. Nonhomeostatic (i.e., pathological) mechanotransduction may play a role in cellular dysfunction in response to mechanical forces through integrin-mediated signaling events, increasing intracellular Ca 2+ concentration, causing membrane disruption via protein phosphory-D. Kacy Cullen and M. Christian Lessing contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Collagen-Dependent Neurite Outgrowth and Response to Dynamic Deformation in Three-Dimensional Neuronal Cultures

2007

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Abstract-In vitro models of brain injury that use thick 3-D cultures and control extracellular matrix constituents allow evaluation of cell-matrix interactions in a more physiologically relevant configuration than traditional 2-D cultures. We have developed a 3-D cell culture system consisting of primary rat cortical neurons distributed throughout thick (>500 lm) gels consisting of type IV collagen (Col) conjugated to agarose. Neuronal viability and neurite outgrowth were examined for a range of agarose (AG) percentages (1.0-3.0%) and initial collagen concentrations ([Col] i ; 0-600 lg/ mL). In unmodified AG, 1.5% gels supported viable cultures with significant neurite outgrowth, which was not found at lower (£1.0%) concentrations. Varying [Col] 30, 150, and 300 lg/mL, which supported cultures with similar baseline viability and neurite outgrowth. Conjugation of Col to AG also increased the complex modulus of the hydrogel. Following high rate deformation, neuronal viability significantly decreased with increasing [Col] i , implicating cell-matrix adhesions in acute mechanotransduction events associated with traumatic loading. These results suggest interrelated roles for matrix mechanical properties and receptor-mediated cell-matrix interactions in neuronal viability, neurite outgrowth, and transduction of high rate deformation. This model system may be further exploited for the elucidation of mechanotransduction mechanisms and cellular pathology following mechanical insult.

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“…Focal adhesion complexes and adherens junctions (through which cells interact with the substrate and each other, respectively) have been argued as the likely loci of mechanosensation (22,23). There is evidence for mechanical stress-induced ectopic expression of genes in Drosophila embryo (24), which appears to be mediated by Armadillo, a protein that in one of its roles serves as a scaffold for the assembly of cell-adhesion junctions with cortical actin (25,26).…”

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confidence: 99%

Mechanical feedback as a possible regulator of tissue growth

Shraiman

2005

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

573

517

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Regulation of cell growth and proliferation has a fundamental role in animal and plant development and in the progression of cancer. In the context of development, it is important to understand the mechanisms that coordinate growth and patterning of tissues. Imaginal discs, which are larval precursors of fly limbs and organs, have provided much of what we currently know about these processes. Here, we consider the mechanism that is responsible for the observed uniformity of growth in wing imaginal discs, which persists in the presence of gradients in growth inducing morphogens in spite of the stochastic nature of cell division. The phenomenon of ''cell competition,'' which manifests in apoptosis of slowergrowing cells in the vicinity of faster growing tissue, suggests that uniform growth is not a default state but a result of active regulation. How can a patch of tissue compare its growth rate with that of its surroundings? A possible way is furnished by mechanical interactions. To demonstrate this mechanism, we formulate a mathematical model of nonuniform growth in a layer of tissue and examine its mechanical implications. We show that a clone growing faster or slower than the surrounding tissue is subject to mechanical stress, and we propose that dependence of the rate of cell division on local stress could provide an ''integral-feedback'' mechanism stabilizing uniform growth. The proposed mechanism of growth control is not specific to imaginal disc growth and could be of general relevance. Several experimental tests of the proposed mechanism are suggested.Drosophila melanogaster ͉ imaginal disc ͉ mechanics ͉ stress U nderstanding the principles and mechanisms involved in animal and plant development remains an outstanding challenge for modern biology (1, 2). Among the fundamental problems is the problem of understanding how organisms (or organs and body parts) coordinate their growth with internal patterning to achieve correct size and proportions (3-5). A fruit fly, Drosophila melanogaster, has been an invaluable model of development in general and organogenesis in particular (6, 7). Below, we focus on the question of growth control (8, 9) in the context of a wing imaginal disc (7), which is the larval precursor of the adult wing. We point out that nonuniform growth in a layer of cells that adhere to each other (as is the case for imaginal discs) leads to accumulation of mechanical stress. This stress may provide cells with a feedback signal, regulating cell division and insuring stable and uniform growth of tissue. To describe this process quantitatively, we formulate and analyze a mathematical model of mechanical deformation in growing tissue. We show that the proposed mechanical feedback model could naturally explain certain salient features of growth in imaginal discs, such as ''cell competition'' (6, 10, 11), and suggest experiments that would directly test the model.The possible role of mechanical interactions in growth has been suggested, most explicitly in the context of plant development (12-15). Ho...

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Intercellular Mechanotransduction: Cellular Circuits That Coordinate Tissue Responses to Mechanical Loading

Cited by 85 publications

References 49 publications

Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures

Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures

Collagen-Dependent Neurite Outgrowth and Response to Dynamic Deformation in Three-Dimensional Neuronal Cultures

Mechanical feedback as a possible regulator of tissue growth

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