scholarly journals Collective cell migration without proliferation: density determines cell velocity and wave velocity

2018 ◽  
Vol 5 (5) ◽  
pp. 172421 ◽  
Author(s):  
Sham Tlili ◽  
Estelle Gauquelin ◽  
Brigitte Li ◽  
Olivier Cardoso ◽  
Benoît Ladoux ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Density ◽  
Wave Velocity ◽  
Cell Monolayer ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Tumour Metastasis ◽  
Long Duration ◽  
Cell Velocity ◽  
Moving Front

Collective cell migration contributes to embryogenesis, wound healing and tumour metastasis. Cell monolayer migration experiments help in understanding what determines the movement of cells far from the leading edge. Inhibiting cell proliferation limits cell density increase and prevents jamming; we observe long-duration migration and quantify space–time characteristics of the velocity profile over large length scales and time scales. Velocity waves propagate backwards and their frequency depends only on cell density at the moving front. Both cell average velocity and wave velocity increase linearly with the cell effective radius regardless of the distance to the front. Inhibiting lamellipodia decreases cell velocity while waves either disappear or have a lower frequency. Our model combines conservation laws, monolayer mechanical properties and a phenomenological coupling between strain and polarity: advancing cells pull on their followers, which then become polarized. With reasonable values of parameters, this model agrees with several of our experimental observations. Together, our experiments and model disantangle the respective contributions of active velocity and of proliferation in monolayer migration, explain how cells maintain their polarity far from the moving front, and highlight the importance of strain–polarity coupling and density in long-range information propagation.

scholarly journals Collective cell migration without proliferation: density determines cell velocity and wave velocity

2017 ◽  
Author(s):  
Sham Tlili ◽  
Estelle Gauquelin ◽  
Brigitte Li ◽  
Olivier Cardoso ◽  
Benoît Ladoux ◽  
...  
Keyword(s):  
Cell Migration ◽  
Wave Velocity ◽  
Signal To Noise Ratio ◽  
Cell Monolayer ◽  
Temporal Analysis ◽  
Collective Cell Migration ◽  
Cell Radius ◽  
Cell Velocity ◽  
Spatio Temporal ◽  
Parameter Values

AbstractCollective cell migration contributes to morphogenesis, wound healing or tumor metastasis. Culturing epithelial monolayers on a substrate enables to quantify such tissue migration. By using narrow strips, we stabilise the front shape; by inhibiting cell division, we limit density increase and favor steady migration; by using long strips, we observe a confined cell monolayer migrating over days. A coherent collective movement propagates over millimeters; cells spread and density decreases from the monolayer bulk toward the front. Cell velocity (∼micrometer per minute) increases linearly with cell radius, and does not depend explicitly on the distance to the front. Over ten periods of backwards propagating velocity waves, with wavelength ∼millimeter, are detected with a signal-to-noise ratio enabling for quantitative spatio-temporal analysis. Their velocity (∼ten micrometers per minute) is ten times the cell velocity; it increases linearly with the cell radius. Their period (∼two hours) is spatially homogeneous, and increases with the front density. When we inhibit the formation of lamellipodia, cell velocity drops while waves either disappear, or have a smaller amplitude and slower period. Our phenomenological model assumes that both cell and wave velocities are related with the activity of lamellipodia, and that the local stretching in the monolayer bulk modulates traction stresses. We find that parameter values close to the instability limit where waves appear yield qualitative and quantitative predictions compatible with experiments, including the facts that: waves propagate backwards; wave velocity increases with cell radius; lamellipodia inhibition attenuates, slows down or even suppresses the waves. Together, our experiments and modelling evidence the importance of lamellipodia in collective cell migration and waves.

scholarly journals CaM kinase IIδ2-dependent regulation of vascular smooth muscle cell polarization and migration

2008 ◽  
Vol 294 (6) ◽  
pp. C1465-C1475 ◽  
Author(s):  
Melissa Z. Mercure ◽  
Roman Ginnan ◽  
Harold A. Singer
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Vascular Smooth Muscle ◽  
Cell Monolayer ◽  
Leading Edge ◽  
Cell Polarization ◽  
Loss Of Function ◽  
Downstream Signaling ◽  
Transient Activation ◽  
And Migration

Previous studies indicate involvement of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) in vascular smooth muscle (VSM) cell migration. In the present study, molecular loss-of-function studies were used specifically to assess the role of the predominant CaMKIIδ2 isoform on VSM cell migration using a scratch wound healing assay. Targeted CaMKIIδ2 knockdown using siRNA or inhibition of activity by overexpressing a kinase-negative mutant resulted in attenuation of VSM cell migration. Temporal and spatial assessments of kinase autophosphorylation indicated rapid and transient activation in response to wounding, in addition to a sustained activation in the leading edge of migrating and spreading cells. Furthermore, siRNA-mediated suppression of CaMKIIδ2 resulted in the inhibition of wound-induced Rac activation and Golgi reorganization, and disruption of leading edge morphology, indicating an important function for CaMKIIδ2 in regulating VSM cell polarization. Numerous previous reports link activation of CaMKII to ERK1/2 signaling in VSM. Wound-induced ERK1/2 activation was also found to be dependent on CaMKII; however, ERK activity did not account for effects of CaMKII in regulating Golgi polarization, indicating alternative mechanisms by which CaMKII affects the complex events involved in cell migration. Wounding a VSM cell monolayer results in CaMKIIδ2 activation, which positively regulates VSM cell polarization and downstream signaling, including Rac and ERK1/2 activation, leading to cell migration.

scholarly journals α4/α9 Integrins Coordinate Epithelial Cell Migration Through Local Suppression of MAP Kinase Signaling Pathways

2021 ◽  
Vol 9 ◽  
Author(s):  
Willow Hight-Warburton ◽  
Robert Felix ◽  
Andrew Burton ◽  
Hannah Maple ◽  
Magda S. Chegkazi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Complexes ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Keratinocyte Proliferation ◽  
Basal Keratinocytes ◽  
Keratinocyte Cell

Adhesion of basal keratinocytes to the underlying extracellular matrix (ECM) plays a key role in the control of skin homeostasis and response to injury. Integrin receptors indirectly link the ECM to the cell cytoskeleton through large protein complexes called focal adhesions (FA). FA also function as intracellular biochemical signaling platforms to enable cells to respond to changing extracellular cues. The α4β1 and α9β1 integrins are both expressed in basal keratinocytes, share some common ECM ligands, and have been shown to promote wound healing in vitro and in vivo. However, their roles in maintaining epidermal homeostasis and relative contributions to pathological processes in the skin remain unclear. We found that α4β1 and α9β1 occupied distinct regions in monolayers of a basal keratinocyte cell line (NEB-1). During collective cell migration (CCM), α4 and α9 integrins co-localized along the leading edge. Pharmacological inhibition of α4β1 and α9β1 integrins increased keratinocyte proliferation and induced a dramatic change in cytoskeletal remodeling and FA rearrangement, detrimentally affecting CCM. Further analysis revealed that α4β1/α9β1 integrins suppress extracellular signal-regulated kinase (ERK1/2) activity to control migration through the regulation of downstream kinases including Mitogen and Stress Activated Kinase 1 (MSK1). This work demonstrates the roles of α4β1 and α9β1 in regulating migration in response to damage cues.

scholarly journals Integrin α5β1 nano-presentation regulates collective keratinocyte migration independent of substrate rigidity

2021 ◽  
Author(s):  
Jacopo Di Russo ◽  
Jennifer L. Young ◽  
Julian W. R. Wegner ◽  
Timmy Steins ◽  
Horst Kessler ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Cell Monolayer ◽  
Collective Cell Migration ◽  
Integrin Α5β1 ◽  
Migration Ability ◽  
Fibronectin Receptor ◽  
Substrate Rigidity ◽  
Scale Properties ◽  
Extracellular Matrix Receptors

AbstractNanometer-scale properties of the extracellular matrix influence many biological processes, including cell motility. While much information is available for single cell migration, to date, no knowledge exists on how the nanoscale presentation of extracellular matrix receptors influences collective cell migration. In wound healing, basal keratinocytes collectively migrate on a fibronectin-rich provisional basement membrane to re-epithelialize the injured skin. Among other receptors, the fibronectin receptor integrin α5β1 plays a pivotal role in this process. Using a highly specific integrin α5β1 peptidomimetic combined with nanopatterned hydrogels, we show that keratinocyte sheets regulate their migration ability at an optimal integrin α5β1 nanospacing. This efficiency relies on the effective propagation of stresses within the cell monolayer independent of substrate stiffness. For the first time, this work highlights the importance of extracellular matrix receptor nanoscale organization required for efficient tissue regeneration.

scholarly journals Mechanochemical coupling and junctional forces during collective cell migration

2019 ◽  
Author(s):  
J. Bui ◽  
D. E. Conway ◽  
R. L. Heise ◽  
S.H. Weinberg
Keyword(s):  
Cell Migration ◽  
Rho Gtpases ◽  
Cancer Metastasis ◽  
Rho Gtpase ◽  
Critical Role ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Gtpase Activity ◽  
Modeling Framework ◽  
Cell Cell

ABSTRACTCell migration, a fundamental physiological process in which cells sense and move through their surrounding physical environment, plays a critical role in development and tissue formation, as well as pathological processes, such as cancer metastasis and wound healing. During cell migration, dynamics are governed by the bidirectional interplay between cell-generated mechanical forces and the activity of Rho GTPases, a family of small GTP-binding proteins that regulate actin cytoskeleton assembly and cellular contractility. These interactions are inherently more complex during the collective migration of mechanically coupled cells, due to the additional regulation of cell-cell junctional forces. In this study, we present a minimal modeling framework to simulate the interactions between mechanochemical signaling in individual cells and interactions with cell-cell junctional forces during collective cell migration. We find that migration of individual cells depends on the feedback between mechanical tension and Rho GTPase activity in a biphasic manner. During collective cell migration, waves of Rho GTPase activity mediate mechanical contraction/extension and thus synchronization throughout the tissue. Further, cell-cell junctional forces exhibit distinct spatial patterns during collective cell migration, with larger forces near the leading edge. Larger junctional force magnitudes are associated with faster collective cell migration and larger tissue size. Simulations of heterogeneous tissue migration exhibit a complex dependence on the properties of both leading and trailing cells. Computational predictions demonstrate that collective cell migration depends on both the emergent dynamics and interactions between cellular-level Rho GTPase activity and contractility, and multicellular-level junctional forces.

scholarly journals In vitro cell migration quantification method for scratch assays

2019 ◽  
Vol 16 (151) ◽  
pp. 20180709 ◽  
Author(s):  
Ana Victoria Ponce Bobadilla ◽  
Jazmine Arévalo ◽  
Eduard Sarró ◽  
Helen M. Byrne ◽  
Philip K. Maini ◽  
...  
Keyword(s):  
Experimental Data ◽  
Cell Migration ◽  
Cell Monolayer ◽  
Leading Edge ◽  
New Method ◽  
Scratch Assay ◽  
Standard Methods ◽  
Migration Rates ◽  
Quantification Method

The scratch assay is an in vitro technique used to assess the contribution of molecular and cellular mechanisms to cell migration. The assay can also be used to evaluate therapeutic compounds before clinical use. Current quantification methods of scratch assays deal poorly with irregular cell-free areas and crooked leading edges which are features typically present in the experimental data. We introduce a new migration quantification method, called ‘monolayer edge velocimetry’, that permits analysis of low-quality experimental data and better statistical classification of migration rates than standard quantification methods. The new method relies on quantifying the horizontal component of the cell monolayer velocity across the leading edge. By performing a classification test on in silico data, we show that the method exhibits significantly lower statistical errors than standard methods. When applied to in vitro data, our method outperforms standard methods by detecting differences in the migration rates between different cell groups that the other methods could not detect. Application of this new method will enable quantification of migration rates from in vitro scratch assay data that cannot be analysed using existing methods.

scholarly journals Collective migration during a gap closure in a two-dimensional haptotactic model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie Versaevel ◽  
Laura Alaimo ◽  
Valentine Seveau ◽  
Marine Luciano ◽  
Danahe Mohammed ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Density ◽  
Healing Process ◽  
Time Lapse ◽  
Wound Healing Process ◽  
Collective Cell Migration ◽  
Two Dimensional ◽  
Gap Closure ◽  
Lower Cell Density ◽  
Protein Gradients

AbstractThe ability of cells to respond to substrate-bound protein gradients is crucial for many physiological processes, such as immune response, neurogenesis and cancer cell migration. However, the difficulty to produce well-controlled protein gradients has long been a limitation to our understanding of collective cell migration in response to haptotaxis. Here we use a photopatterning technique to create circular, square and linear fibronectin (FN) gradients on two-dimensional (2D) culture substrates. We observed that epithelial cells spread preferentially on zones of higher FN density, creating rounded or elongated gaps within epithelial tissues over circular or linear FN gradients, respectively. Using time-lapse experiments, we demonstrated that the gap closure mechanism in a 2D haptotaxis model requires a significant increase of the leader cell area. In addition, we found that gap closures are slower on decreasing FN densities than on homogenous FN-coated substrate and that fresh closed gaps are characterized by a lower cell density. Interestingly, our results showed that cell proliferation increases in the closed gap region after maturation to restore the cell density, but that cell–cell adhesive junctions remain weaker in scarred epithelial zones. Taken together, our findings provide a better understanding of the wound healing process over protein gradients, which are reminiscent of haptotaxis.

scholarly journals Multiscale modelling of motility wave propagation in cell migration

2020 ◽  
Author(s):  
Hamid Khatee ◽  
Andras Czirok ◽  
Zoltan Neufeld
Keyword(s):  
Cell Migration ◽  
Collective Motion ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Tissue Formation ◽  
Cell Monolayers ◽  
Polarization Wave ◽  
Fundamental Biological Process ◽  
Cortical Contractility ◽  
Contractile Cells

AbstractThe collective motion of cell monolayers within a tissue is a fundamental biological process that occurs during tissue formation, wound healing, cancerous invasion, and viral infection. Experiments have shown that at the onset of migration, the motility is self-generated as a polarization wave starting from the leading edge of the monolayer and progressively propagates into the bulk. However, it is unclear how the propagation of this motility wave is influenced by cellular properties. Here, we investigate this using a computational model based on the Potts model coupled to the dynamics of intracellular polarization. The model captures the propagation of the polarization wave initiated at the leading edge and suggests that the cells cortex can regulate the migration modes: strongly contractile cells may depolarize the monolayer, whereas less contractile cells can form swirling movement. Cortical contractility is further found to limit the cells motility, which (i) decelerates the wave speed and the leading edge progression, and (ii) destabilises the leading edge into migration fingers. Together, our model describes how different cellular properties can contribute to the regulation of collective cell migration.

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