Vascular Smooth Muscle Cell Durotaxis Depends on Substrate Stiffness Gradient Strength

Isenberg, Brett C.; DiMilla, Paul A.; Walker, Matthew; Kim, Soo‐Young; Wong, Joyce Y.

doi:10.1016/j.bpj.2009.06.021

Cited by 359 publications

(368 citation statements)

References 47 publications

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“…As cells sense the stiff side, they exert larger forces which in turn could induce a polarization of the actin cytoskeleton toward the stiff side and thus promote durotaxis. Interestingly, qualitatively similar behavior has been observed for the durotaxis of vascular cells on defined stiffness gradients within a range of rigidities up to 80 kPa (47). The study observed a higher polarized behavior on gradient gels than on uniform substrates and a durotactic behavior enhanced by increasing the magnitude of gradients.…”

Section: Dynamics Of Focal Adhesions and Traction Force Measurements Onsupporting

confidence: 80%

Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness

Trichet

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Hawkins

et al. 2012

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

513

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Cell migration plays a major role in many fundamental biological processes, such as morphogenesis, tumor metastasis, and wound healing. As they anchor and pull on their surroundings, adhering cells actively probe the stiffness of their environment. Current understanding is that traction forces exerted by cells arise mainly at mechanotransduction sites, called focal adhesions, whose size seems to be correlated to the force exerted by cells on their underlying substrate, at least during their initial stages. In fact, our data show by direct measurements that the buildup of traction forces is faster for larger substrate stiffness, and that the stress measured at adhesion sites depends on substrate rigidity. Our results, backed by a phenomenological model based on active gel theory, suggest that rigidity-sensing is mediated by a large-scale mechanism originating in the cytoskeleton instead of a local one. We show that large-scale mechanosensing leads to an adaptative response of cell migration to stiffness gradients. In response to a step boundary in rigidity, we observe not only that cells migrate preferentially toward stiffer substrates, but also that this response is optimal in a narrow range of rigidities. Taken together, these findings lead to unique insights into the regulation of cell response to external mechanical cues and provide evidence for a cytoskeleton-based rigidity-sensing mechanism.actin cytoskeleton | microfabrication | mechanobiology | cell mechanics C ell migration is not only sensitive to the biochemical composition of the environment, but also to its mechanical properties. Cells directly probe the physical properties of their environment, such as substrate stiffness, by pulling on it. Increasing evidence show that matrix or tissue elasticity has a key role in regulating numerous cell functions, such as adhesion (1), migration (2) and differentiation (3). Such functions are affected by cell-generated actomyosin forces that depend on substrate stiffness through a feedback mechanism (4). The sensitivity of cells to mechanical properties of the extracellular matrix (ECM) arises from the mechanosensitive nature of cell adhesion. Numerous plausible candidates for the transduction of mechanochemical signals have been tested (5). Among them, focal adhesions (FAs) appear to be the most prominent, as shown by the reported correlation between their area and sustained force exhibiting a constant stress (6-9). This mechanosensitivity is usually accounted for by a generic local mechanism in which a force applied to an FA induces an elastic deformation of the contact that triggers conformational and organizational changes of some of its constitutive proteins, which in turn can enhance binding with new proteins enabling growth of the contact (10-12). However, how this local mechanosensitivity can result in the ability of cells to sense and respond to the rigidity of their surroundings (2, 3, 13, 14) at a large scale remains largely unknown (5, 15). Much conflicting evidence has emerged from a variety of studi...

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Section: Dynamics Of Focal Adhesions and Traction Force Measurements Onsupporting

confidence: 80%

Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness

Trichet

Digabel

Hawkins

et al. 2012

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

513

521

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“…It is known that substrate stiffness largely influences cell migration. Indeed, recent studies have shown that many different types of cells, including VSMCs, move towards stiffer substrates (Isenberg et al, 2009). Therefore, inter-EC junctions might provide the rigid scaffold required for efficient MC migration, because inter-EC junctions are supported by the actin cytoskeleton Phng et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish

et al. 2016

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Mural cells (MCs) consisting of vascular smooth muscle cells and pericytes cover the endothelial cells (ECs) to regulate vascular stability and homeostasis. Here, we clarified the mechanism by which MCs develop and cover ECs by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo. To cover cranial vessels, MCs derived from either neural crest cells or mesoderm emerged around the preformed EC tubes, proliferated and migrated along EC tubes. During their migration, the MCs moved forward by extending their processes along the inter-EC junctions, suggesting a role for inter-EC junctions as a scaffold for MC migration. In the trunk vasculature, MCs derived from mesoderm covered the ventral side of the dorsal aorta (DA), but not the posterior cardinal vein. Furthermore, the MCs migrating from the DA or emerging around intersegmental vessels (ISVs) preferentially covered arterial ISVs rather than venous ISVs, indicating that MCs mostly cover arteries during vascular development. Thus, live imaging and lineage tracing enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs.

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“…It has long been known that the molecular composition of the pericellular environment regulates cell behaviors, but the mechanical properties also mediate cell responses. Cells sense and respond to differences in substrate rigidity, which has been shown to influence behaviors such as growth (2), morphology (3,4), migration (4,5), and differentiation (6 -8), although details of the mechanochemical mechanisms have not been fully elucidated.…”

Section: The Extracellular Matrix (Ecm)mentioning

confidence: 99%

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

Carraher

Schwarzbauer

2013

Journal of Biological Chemistry

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Background: Cell behavior is affected by changes in extracellular matrix stiffness during disease progression. Results: Fibronectin matrix assembly is inhibited on soft substrates but can be restored by manipulating cell-fibronectin binding or by partially unfolding substrate fibronectin. Conclusion: On soft substrates, cells are deficient in integrin-fibronectin bond strength and therefore cannot induce fibronectin conformational changes required for assembly. Significance: Rigidity-dependent changes in fibronectin conformation provide a novel mechanism for mechanotransduction.

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Vascular Smooth Muscle Cell Durotaxis Depends on Substrate Stiffness Gradient Strength

Cited by 359 publications

References 47 publications

Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness

Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness

Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

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