A cytoskeletal clutch mediates cellular force transmission in a soft, three-dimensional extracellular matrix

Owen, Leanna M.; Adhikari, Arjun S.; Patel, Mohak; Grimmer, Peter; Leijnse, Natascha; Kim, Min Cheol; Notbohm, Jacob; Franck, Christian; Dunn, Alexander R.

doi:10.1091/mbc.e17-02-0102

Cited by 67 publications

(71 citation statements)

References 92 publications

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“…In vivo, the nonlinearity of the elastic profile of the ECM is largely governed by degree of hydration and is dependent on the presence of cells as demonstrated by the almost perfectly elastic behavior of acellular, bulk ECM 12. Interestingly, cell‐derived strain‐stiffening of soft (≈200 Pa), fibrous ECM can result in an increase in the local stiffness sensed by neighboring cells, leading to a cell phenotype reminiscent of that observed on gels with E ≈50 kPa 13. These results are in agreement with additional studies that have shown cells seeded on soft, nonlinear elastic matrices show large cell areas (a hallmark of active mechanotransduction on stiff substrates) equivalent to those observed on stiff, linear elastic matrix 14,15.…”

Section: The Extracellular Matrix: Foundations Of Matrix Mechanics Ansupporting

confidence: 86%

“…Recently, there have been growing efforts to extend the observations reported in 2D clutch models to 3D systems. Though still largely unexplored, preliminary studies have revealed that a second cytoskeletal clutch may exist in the 3D environment that cooperates with the previously mentioned 2D clutch system to elongate stress fibers anchored at FAs, providing migrating cells a mechanism of maintaining consistent attachment to ECM throughout locomotion 13. Further studies that continue to expand 2D clutch observations into three‐dimensions will likely lead to exciting discoveries that extend current understandings of the molecular clutch to in vivo processes.…”

Section: The Extracellular Matrix: Foundations Of Matrix Mechanics Anmentioning

confidence: 99%

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Feeling Things Out: Bidirectional Signaling of the Cell–ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation

Miller

Barker

2020

Adv Healthcare Materials

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Biophysical cues stemming from the extracellular environment are rapidly transduced into discernible chemical messages (mechanotransduction) that direct cellular activities-placing the extracellular matrix (ECM) as a potent regulator of cell behavior. Dynamic reciprocity between the cell and its associated matrix is essential to the maintenance of tissue homeostasis and dysregulation of both ECM mechanical signaling, via pathological ECM turnover, and internal mechanotransduction pathways contribute to disease progression. This review covers the current understandings of the key modes of signaling used by both the cell and ECM to coregulate one another. By taking an outside-in approach, the inherent complexities and regulatory processes at each level of signaling (ECM, plasma membrane, focal adhesion, and cytoplasm) are captured to give a comprehensive picture of the internal and external mechanoregulatory environment. Specific emphasis is placed on the focal adhesion complex which acts as a central hub of mechanical signaling, regulating cell spreading, migration, proliferation, and differentiation. In addition, a wealth of available knowledge on mechanotransduction is curated to generate an integrated signaling network encompassing the central components of the focal adhesion, cytoplasm and nucleus that act in concert to promote durotaxis, proliferation, and differentiation in a stiffness-dependent manner.

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Section: The Extracellular Matrix: Foundations Of Matrix Mechanics Ansupporting

confidence: 86%

Section: The Extracellular Matrix: Foundations Of Matrix Mechanics Anmentioning

confidence: 99%

Feeling Things Out: Bidirectional Signaling of the Cell–ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation

Miller

Barker

2020

Adv Healthcare Materials

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“…As such, retrograde flow inversely correlates with cell migration speed . The flow is partially transmitted to adaptor proteins and integrins, meaning molecules closer to the ECM experience progressively slower retrograde speeds . Retrograde flow is observed for different types of actin structures, from lamellipodia to stress fibers, and similarly in cadherin‐based cell–cell adhesions .…”

Section: Mechanotransduction At the Cell–matrix Interfacementioning

confidence: 99%

The Plot Thickens: The Emerging Role of Matrix Viscosity in Cell Mechanotransduction

Cantini

Donnelly

Dalby

et al. 2019

Adv Healthcare Materials

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Cell mechanotransduction is an area of intense research focus. Until now, very limited tools have existed to study how cells respond to changes in the extracellular matrix beyond, for example, mechanical deformation studies and twisting cytometry. However, emerging are a range of elastic, viscoelastic and even purely viscous materials that deform and dissipate on cellular length and timescales. This article reviews developments in these materials, typically translating from 2D model surfaces to 3D microenvironments and explores how cells interact with them. Specifically, it focuses on emerging concepts such as the molecular clutch model, how different extracellular matrix proteins engage the clutch under viscoelastic‐stress relaxation conditions, and how mechanotransduction can drive transcriptional control through regulators such as YAP/TAZ.

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“…Drawing on previous work (Simson et al, 1998), we experimentally decreased apical surface bending energy with a cocktail of inhibitors (1 µM latrunculin A, 20 µM ML-7, 20 µM Y-27632, and 50 µM nocodazole) that works to acutely ablate the actomyosin and microtubule cytoskeletons (Owen et al, 2017) (Supplementary Video 1). Remarkably, lumen face shapes were largely unaffected by cytoskeletal ablation (Fig.…”

Section: Cells Regulate Both Luminal Pressure and Surface Area To Defmentioning

confidence: 99%

Physical basis of lumen shape and stability in a simple epithelium

Vasquez

Vachharajani

Garzón-Coral

et al. 2019

Preprint

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A continuous sheet of epithelial cells surrounding a hollow opening, or lumen, defines the basic topology of numerous organs. De novo lumen formation is a central feature of embryonic development whose dysregulation leads to congenital and acquired diseases of the kidney and other organs. While prior work has described the hydrostatic pressure-driven expansion of lumens when they are large, the physical mechanisms that promote the formation and maintenance of small, nascent lumens are less explored. In particular, models that rely solely on pressure-driven expansion face a potential challenge in that the Laplace pressure, which resists lumen expansion, is predicted to scale inversely with lumen radius. We investigated the cellular and physical mechanisms responsible for stabilizing the initial stages of lumen growth using a 3D culture system in which epithelial cells spontaneously form hollow lumens. Our experiments revealed that neither the actomyosin nor microtubule cytoskeletons are required to stabilize lumen geometry, and that a positive intraluminal pressure is not necessary for lumen stability. Instead, our observations are in agreement with a quantitative model in which cells maintain lumen shape due to topological and geometrical factors tied to the establishment of apicobasolateral polarity. We suggest that this model may provide a general physical mechanism for the formation of luminal openings in a variety of physiological contexts. Lumen shapes for small-and intermediate-size MDCK spheroids are inconsistent with a Laplace model of lumen stabilityWe seeded MDCK cells expressing a fluorescent marker for actin filaments (Lifeact-RFP) in the recombinant extracellular matrix Matrigel. Under these culture conditions, MDCK cells spontaneously form hollow spheroids within 24 hours. To obtain high-resolution images of nascent lumens, we imaged young (18-24 hours) spheroids using lattice light sheet microscopy (LLSM). This acquisition method produced images in which the two opposing apical cortices of the lumen are clearly distinguishable and separated by ~200-300 nm (Fig. 1b,c). We infer that cellular apical surfaces are intrinsically non-adherent, as even small fluctuations in cell shape would allow apposing apical surfaces to contact and potentially adhere. This "non-stick" behavior may reflect the enrichment of negatively charged sialoglycoproteins such as

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A cytoskeletal clutch mediates cellular force transmission in a soft, three-dimensional extracellular matrix

Abstract: Quantitative analysis of the pairwise dynamics of the actin cytoskeleton, focal adhesions, and ECM fibrils reveals how cytoskeletal dynamics drive matrix deformation and cell motility for primary human fibroblasts embedded in a 3D fibrin matrix.

Cited by 67 publications

References 92 publications

Feeling Things Out: Bidirectional Signaling of the Cell–ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation

Feeling Things Out: Bidirectional Signaling of the Cell–ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation

The Plot Thickens: The Emerging Role of Matrix Viscosity in Cell Mechanotransduction

Physical basis of lumen shape and stability in a simple epithelium

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