Topographic confinement of epithelial clusters induces epithelial-to-mesenchymal transition in compliant matrices

Nasrollahi, Samila; Pathak, Amit

doi:10.1038/srep18831

Cited by 53 publications

(88 citation statements)

References 42 publications

(76 reference statements)

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“…3 a. Thus, the stiffness matters less in narrow channels, which is consistent with our experimental findings (9). The ECM confinement matters more in softer environments, as evidenced by the diverging trend-lines toward the lower ECM stiffness regime in Fig.…”

Section: Resultssupporting

confidence: 90%

“…The model also accounts for stiffness and geometry of the ECM surrounding the multicell network. We test the model for varying ECM stiffness (0.1-1000 kPa) and confinement due to channel widths between 20 and 80 mm, emulating several previous experiments (1)(2)(3)(4)9,13). Consistent with the known ability of cells to actively respond to ECM stiffness (3,4,14), our model predicts that cell clusters scatter more readily on stiffer ECMs.…”

Section: Introductionmentioning

confidence: 56%

“…Our recent experiments revealed that epithelial clusters disintegrate more readily in confined environments even in soft ECMs (9). When the cells were rendered unable to extend protrusions or polarize, by inhibiting the function of microtubules, this confinement-dependent EMT vanished.…”

Section: Introductionmentioning

confidence: 94%

“…The system of ordinary differential equations (ODEs) developed above (Eqs. 1, 5, and 6), corresponding to CE adhesions a, CC junctions b, cellular adhesion node position x c , and nuclear node position x n , is solved using Runge-Kutta scheme from time t ¼ 0-120 h, consistent with experimental culture period (1)(2)(3)(4)9). As the CE adhesions grow (Eq.…”

Section: Simulation Of Cell Clusters In Defined Ecmsmentioning

confidence: 99%

“…Consistent with the known ability of cells to actively respond to ECM stiffness (3,4,14), our model predicts that cell clusters scatter more readily on stiffer ECMs. Surprisingly, the cells trapped within 2D islands do not undergo scattering (13) as they do inside 3D channels with vertical walls (9). After the inhibition of microtubules-based protrusions and cell polarization, cell clusters exhibit a confinement-insensitive behavior.…”

Section: Introductionmentioning

confidence: 99%

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Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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Epithelial-to-mesenchymal transition (EMT) enables scattering of cell clusters and disseminates motile cells to distant locations in vivo during embryonic development and cancer metastasis. Both stiffness and topography of the extracellular matrix (ECM) have been shown to influence EMT. In this work, we examine how the integrity of epithelial cell clusters is regulated by subcellular forces, protrusions, and adhesions for varying ECM inputs, such as stiffness, topography, and dimensionality. Our model simulates multicell networks of defined sizes and shapes in ECMs of varied stiffness and geometry. The integrity of cell clusters is dictated by cell-cell junctions, which depend on subcellular forces and adhesion dynamics within each cell of the cluster. Our simulations demonstrate an enhanced dissociation of cell-cell junctions in stiffer and more confined three-dimensional (3D) environments, consistent with experimental findings. In narrow channels, the cell edges parallel to the axis of channels lose their cell-cell junctions more readily than those oriented in the perpendicular direction. The inhibition of protrusive activity and cell polarity disables confinement-dependent cell scattering. Here, cell adhesion and spreading along channel walls is found to be essential for scattering. The model also predicts that two-dimensional (2D) confinement of clusters restricts cell spreading and simultaneously blunts the confinement-sensitive cell scattering. This new, to our knowledge, multiscale model integrates molecular adhesion dynamics, subcellular forces, cellular deformation, and macroscale mechanical properties of the ECM to predict the state of cell clusters of defined shapes and sizes. The predictions made by our model not only match experimental findings from a number of experimental setups, but also provide a new conceptual framework for understanding mechanosensitive cell scattering and EMT.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 94%

Section: Simulation Of Cell Clusters In Defined Ecmsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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Endothelial Cell Mechanotransduction in the Dynamic Vascular Environment

2018

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The vascular endothelial cells (ECs) that line the inner layer of blood vessels are responsible for maintaining vascular homeostasis under physiological conditions. In the presence of disease or injury, ECs can become dysfunctional and contribute to a progressive decline in vascular health. ECs are constantly exposed to a variety of dynamic mechanical stimuli, including hemodynamic shear stress, pulsatile stretch, and passive signaling cues derived from the extracellular matrix. This review describes the molecular mechanisms by which ECs perceive and interpret these mechanical signals. The translational applications of mechanosensing are then discussed in the context of endothelial-to-mesenchymal transition and engineering of vascular grafts.

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