Publications

Directed cell migration is an essential building block of life, present when an embryo develops, a dendritic cell migrates toward a lymphatic vessel, or a fibrotic organ fails to restore its normal parenchyma. Directed cell migration is often guided by spatial gradients in a physicochemical property of the cell microenvironment, such as a gradient in chemical factors dissolved in the medium or a gradient in the mechanical properties of the substrate. Single cells and tissues sense these gradients, establish a back-to-front polarity, and coordinate the migration machinery accordingly. Central to these steps we find physical forces. In some cases, these forces are integrated into the gradient sensing mechanism. Other times, they transmit information through cells and tissues to coordinate a collective response. At any time, they participate in the cellular migratory system. In this review, we explore the role of physical forces in gradient sensing, polarization, and coordinating movement from single cells to multicellular collectives. We use the framework proposed by the molecular clutch model and explore to what extent asymmetries in the different elements of the clutch can lead to directional migration.

JTD Keywords: Cell migration, Cell traction forces, Chemotaxis, Contact guidance, Curvotaxis, Cytoskeleton, Durotaxis, Extracellular-matrix, Focal adhesions, Guidance, Haptotaxis, Leading-edge, Mechanotaxis, Membrane tension, Molecular clutch model, Myosin-ii, Reduced inequalities, Rigidity, Stress fibers, Traction

Several factors present in the extracellular environment regulate epithelial cell adhesion and dynamics. Among them, growth factors such as EGF, upon binding to their receptors at the cell surface, get internalized and directly activate the acto-myosin machinery. In this study we present the effects of EGF on the contractility of epithelial cancer cell colonies in confined geometry of different sizes. We show that the extent to which EGF triggers contractility scales with the cluster size and thus the number of cells. Moreover, the collective contractility results in a radial distribution of traction forces, which are dependent on integrin β1 peripheral adhesions and transmitted to neighboring cells through adherens junctions. Taken together, EGF-induced contractility acts on the mechanical crosstalk and linkage between the cell-cell and cell-matrix compartments, regulating collective responses.Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.

JTD Keywords: actin, activation, actomyosin, adherens junctions, adhesion, e-cadherin, egf, maturation, mechanical regulation, micropatterning, migration, traction forces, transduction, transmission, Actomyosin, Adherens junctions, Cell adhesion, Cell membrane, Collective contractility, Egf, Epidermal growth factor, Epidermal-growth-factor, Epithelial cells, Micropatterning, Myosins, Traction forces

Calcium signaling participates in different cellular processes leading to cell migration. TRPV4, a non-selective cation channel that responds to mechano-osmotic stimulation and heat, is also involved in cell migration. However, the mechanistic involvement of TRPV4 in cell migration is currently unknown. We now report that expression of the mutant channel TRPV4-121AAWAA (lacking the phosphoinositide-binding site 121KRWRK125 and the response to physiological stimuli) altered HEK293 cell migration. Altered migration patterns included periods of fast and persistent motion followed by periods of stalling and turning, and the extension of multiple long cellular protrusions. TRPV4-WT overexpressing cells showed almost complete loss of directionality with frequent turns, no progression, and absence of long protrusions. Traction microscopy revealed higher tractions forces in the tail of TRPV4-121AAWAA than in TRPV4-WT expressing cells. These results are consistent with a defective and augmented tail retraction in TRPV4-121AAWAA- and TRPV4-WT-expressing cells, respectively. The activity of calpain, a protease implicated in focal adhesion (FA) disassembly, was decreased in TRPV4-121AAWAA compared with TRPV4-WT-expressing cells. Consistently, larger focal adhesions were seen in TRPV4-121AAWAA compared with TRPV4-WT-expressing HEK293 cells, a result that was also reproduced in T47D and U87 cells. Similarly, overexpression of the pore-dead mutant TRPV4-M680D resumed the TRPV4-121AAWAA phenotype presenting larger FA. The migratory phenotype obtained in HEK293 cells overexpressing TRPV4-121AAWAA was mimicked by knocking-down TRPC1, a cationic channel that participates in cell migration. Together, our results point to the participation of TRPV4 in the dynamics of trailing adhesions, a function that may require the interplay of TRPV4 with other cation channels or proteins present at the FA sites.

JTD Keywords: Calcium, Calpain, Focal adhesion, Migration, Traction forces, TRPV4

Matrix and tissue rigidity guides many cellular processes, including the differentiation of stem cells and the migration of cells in health and disease. Cells actively and transiently test rigidity using mechanisms limited by inherent physical parameters that include the strength of extracellular attachments, the pulling capacity on these attachments, and the sensitivity of the mechanotransduction system. Here, we focus on rigidity sensing mediated through the integrin family of extracellular matrix receptors and linked proteins and discuss the evidence supporting these proteins as mechanosensors.

JTD Keywords: Focal adhesion kinase, Atomic Force Microscopy, Smooth-muscle cells, Traction forces, Living cells, Mechanical force, Locomoting cells