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Journal ArticleDOI

Fibroblast Adaptation and Stiffness Matching to Soft Elastic Substrates

15 Dec 2007-Biophysical Journal (The Biophysical Society)-Vol. 93, Iss: 12, pp 4453-4461
TL;DR: Within a range of stiffness spanning that of soft tissues, fibroblasts tune their internal stiffness to match that of their substrate, and modulation of cellular stiffness by the rigidity of the environment may be a mechanism used to direct cell migration and wound repair.
About: This article is published in Biophysical Journal.The article was published on 2007-12-15 and is currently open access. It has received 999 citations till now. The article focuses on the topics: Stiffness.
Citations
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Journal ArticleDOI
TL;DR: The changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.
Abstract: Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

1,706 citations


Cites background from "Fibroblast Adaptation and Stiffness..."

  • ...The magnitude of cellular contractility reflects the cell type and stat...

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Journal ArticleDOI
TL;DR: The metastatic process is reconstructed and the importance of key physical and mechanical processes at each step of the cascade is described, which may help to solve some long-standing questions in disease progression and lead to new approaches to developing cancer diagnostics and therapies.
Abstract: Metastasis is a complex, multistep process responsible for >90% of cancer-related deaths. In addition to genetic and external environmental factors, the physical interactions of cancer cells with their microenvironment, as well as their modulation by mechanical forces, are key determinants of the metastatic process. We reconstruct the metastatic process and describe the importance of key physical and mechanical processes at each step of the cascade. The emerging insight into these physical interactions may help to solve some long-standing questions in disease progression and may lead to new approaches to developing cancer diagnostics and therapies.

1,073 citations

Journal ArticleDOI
TL;DR: Insight is provided of how substrate stiffness differentially regulates stem cell differentiation, and have significant implications for the design of biomaterials with appropriate mechanical property for tissue regeneration.

677 citations


Cites background from "Fibroblast Adaptation and Stiffness..."

  • ...When cells generate traction forces higher than what the substrate can withstand, the matrix may yield and cells could adapt by decreasing the traction force, integrin binding and their own stiffness [16,17], which modulate cell spreading and thus differentiation [18,19]....

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Journal ArticleDOI
TL;DR: The overview of the available methods to study cell adhesion through attachment and detachment events was discussed, which included the cell population and single cell approach.
Abstract: Cell adhesion is essential in cell communication and regulation, and is of fundamental importance in the development and maintenance of tissues. The mechanical interactions between a cell and its extracellular matrix (ECM) can influence and control cell behavior and function. The essential function of cell adhesion has created tremendous interests in developing methods for measuring and studying cell adhesion properties. The study of cell adhesion could be categorized into cell adhesion attachment and detachment events. The study of cell adhesion has been widely explored via both events for many important purposes in cellular biology, biomedical, and engineering fields. Cell adhesion attachment and detachment events could be further grouped into the cell population and single cell approach. Various techniques to measure cell adhesion have been applied to many fields of study in order to gain understanding of cell signaling pathways, biomaterial studies for implantable sensors, artificial bone and tooth replacement, the development of tissue-on-a-chip and organ-on-a-chip in tissue engineering, the effects of biochemical treatments and environmental stimuli to the cell adhesion, the potential of drug treatments, cancer metastasis study, and the determination of the adhesion properties of normal and cancerous cells. This review discussed the overview of the available methods to study cell adhesion through attachment and detachment events.

620 citations

Journal ArticleDOI
TL;DR: It is shown that a local cyclic stress via focal adhesions induced spreading in mouse ES cells but not in mES cell-differentiated (ESD) cells that were 10-fold stiffer, demonstrating that cell softness dictates cellular sensitivity to force.
Abstract: Growing evidence suggests that physical microenvironments and mechanical stresses, in addition to soluble factors, help direct mesenchymal-stem-cell fate. However, biological responses to a local force in embryonic stem cells remain elusive. Here we show that a local cyclic stress through focal adhesions induced spreading in mouse embryonic stem cells but not in mouse embryonic stem-cell-differentiated cells, which were ten times stiffer. This response was dictated by the cell material property (cell softness), suggesting that a threshold cell deformation is the key setpoint for triggering spreading responses. Traction quantification and pharmacological or shRNA intervention revealed that myosin II contractility, F-actin, Src or cdc42 were essential in the spreading response. The applied stress led to oct3/4 gene downregulation in mES cells. Our findings demonstrate that cell softness dictates cellular sensitivity to force, suggesting that local small forces might have far more important roles in early development of soft embryos than previously appreciated.

509 citations

References
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Journal ArticleDOI
25 Aug 2006-Cell
TL;DR: Naive mesenchymal stem cells are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types.

12,204 citations


"Fibroblast Adaptation and Stiffness..." refers background or methods in this paper

  • ...(A) Rhodamine-phalloidin staining of the F-actin of fixed fibroblasts on a 1-kPa gel (1), 5-kPa gel ( 2 ), 10-kPa gel (3), and glass (4)....

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  • ...For example, mesenchymal stem cells can be differentiated into neurogenic, myogenic, or osteogenic cell types by varying the magnitude of matrix stiffness to mimic that of the native tissue ( 2 )....

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Journal ArticleDOI
18 Nov 2005-Science
TL;DR: An understanding of how tissue cells—including fibroblasts, myocytes, neurons, and other cell types—sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels with which elasticity can be tuned to approximate that of tissues.
Abstract: Normal tissue cells are generally not viable when suspended in a fluid and are therefore said to be anchorage dependent. Such cells must adhere to a solid, but a solid can be as rigid as glass or softer than a baby's skin. The behavior of some cells on soft materials is characteristic of important phenotypes; for example, cell growth on soft agar gels is used to identify cancer cells. However, an understanding of how tissue cells-including fibroblasts, myocytes, neurons, and other cell types-sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels (or to other cells) with which elasticity can be tuned to approximate that of tissues. Key roles in molecular pathways are played by adhesion complexes and the actinmyosin cytoskeleton, whose contractile forces are transmitted through transcellular structures. The feedback of local matrix stiffness on cell state likely has important implications for development, differentiation, disease, and regeneration.

5,889 citations


"Fibroblast Adaptation and Stiffness..." refers background or methods in this paper

  • ...These responses are cell-type dependent in that the effective range of substrate rigidity depends on the tissue type from which the cells are derived (4)....

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  • ...(A) Rhodamine-phalloidin staining of the F-actin of fixed fibroblasts on a 1-kPa gel (1), 5-kPa gel (2), 10-kPa gel (3), and glass (4)....

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Journal ArticleDOI
TL;DR: It is found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation.

3,553 citations


"Fibroblast Adaptation and Stiffness..." refers background in this paper

  • ...Stimulated contractility leads to an increase in the stress applied to cellular substrates (7,11), which has been shown to regulate the activity of small GTPases and the formation of focal adhesions (10,12)....

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  • ...Cells grown on stiff substrates assemble actin stress fibers (5), exhibit a more spread phenotype (3), upregulate the expression of integrins (6), modify the properties and composition of their substrate adhesions (3,7,8), and activate signaling pathways characteristic of contractility (7,9,10)....

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  • ...The model also predicts that the stress between a fully spread cell and the gel will increase with gel stiffness, as was recently shown by traction force experiments (7,47)....

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  • ...(7,8,12,24), and these changes in turn can alter the assembly state of the cytoskeleton and the tension imposed on it by activated myosins or other motors....

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Journal ArticleDOI
TL;DR: It is discovered that changes in tissue rigidity and strain could play an important controlling role in a number of normal and pathological processes involving cell locomotion, including morphogenesis, the immune response, and wound healing.

3,189 citations


"Fibroblast Adaptation and Stiffness..." refers background in this paper

  • ...Additionally, if stiffer substrates allow more cell deformation than softer ones, as our model predicts, cells will tend to spread and migrate into stiffer regions, a phenomenon known as durotaxis that has been observed experimentally (19)....

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Journal ArticleDOI
TL;DR: The ability of cells to survey the mechanical properties of their surrounding environment is demonstrated and the possible involvement of both protein tyrosine phosphorylation and myosin-generated cortical forces in this process is suggested.
Abstract: Responses of cells to mechanical properties of the adhesion substrate were examined by culturing normal rat kidney epithelial and 3T3 fibroblastic cells on a collagen-coated polyacrylamide substrate that allows the flexibility to be varied while maintaining a constant chemical environment. Compared with cells on rigid substrates, those on flexible substrates showed reduced spreading and increased rates of motility or lamellipodial activity. Microinjection of fluorescent vinculin indicated that focal adhesions on flexible substrates were irregularly shaped and highly dynamic whereas those on firm substrates had a normal morphology and were much more stable. Cells on flexible substrates also contained a reduced amount of phosphotyrosine at adhesion sites. Treatment of these cells with phenylarsine oxide, a tyrosine phosphatase inhibitor, induced the formation of normal, stable focal adhesions similar to those on firm substrates. Conversely, treatment of cells on firm substrates with myosin inhibitors 2,3-butanedione monoxime or KT5926 caused the reduction of both vinculin and phosphotyrosine at adhesion sites. These results demonstrate the ability of cells to survey the mechanical properties of their surrounding environment and suggest the possible involvement of both protein tyrosine phosphorylation and myosin-generated cortical forces in this process. Such response to physical parameters likely represents an important mechanism of cellular interaction with the surrounding environment within a complex organism.

3,013 citations


"Fibroblast Adaptation and Stiffness..." refers background or methods in this paper

  • ...Cells grown on stiff substrates assemble actin stress fibers (5), exhibit a more spread phenotype (3), upregulate the expression of integrins (6), modify the properties and composition of their substrate adhesions (3,7,8), and activate signaling pathways characteristic of contractility (7,9,10)....

    [...]

  • ...(A) Rhodamine-phalloidin staining of the F-actin of fixed fibroblasts on a 1-kPa gel (1), 5-kPa gel (2), 10-kPa gel (3), and glass (4)....

    [...]