Collective Cell Migration: A Mechanistic Perspective

Physiology ◽  
2013 ◽  
Vol 28 (6) ◽  
pp. 370-379 ◽  
Author(s):  
Sri Ram Krishna Vedula ◽  
Andrea Ravasio ◽  
Chwee Teck Lim ◽  
Benoit Ladoux
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Social Behavior ◽  
Cancer Metastasis ◽  
Collective Cell Migration ◽  
Biological Processes ◽  
The Social ◽  
Holistic Understanding ◽  
Broad Overview

Collective cell migration is fundamental to gaining insights into various important biological processes such as wound healing and cancer metastasis. In particular, recent in vitro studies and in silico simulations suggest that mechanics can explain the social behavior of multicellular clusters to a large extent with minimal knowledge of various cellular signaling pathways. These results suggest that a mechanistic perspective is necessary for a comprehensive and holistic understanding of collective cell migration, and this review aims to provide a broad overview of such a perspective.

scholarly journals Viscoelasticity and cell jamming state transition

2021 ◽  
Author(s):  
Ivana Pajic-Lijakovic ◽  
Milan Milivojevic
Keyword(s):  
Residual Stress ◽  
Wound Healing ◽  
Cell Migration ◽  
State Transition ◽  
State Transitions ◽  
Collective Cell Migration ◽  
Biological Processes ◽  
Cell Mobility ◽  
Controversial Topic ◽  
The Impact

Although collective cell migration (CCM) is a highly coordinated migratory mode, perturbations in the form of jamming state transitions and vice versa often occur even in 2D. These perturbations are involved in various biological processes, such as embryogenesis, wound healing and cancer invasion. CCM induces accumulation of cell residual stress which has a feedback impact to cell packing density. Density-mediated change of cell mobility influences the state of viscoelasticity of multicellular systems and on that base the jamming state transition. Although a good comprehension of how cells collectively migrate by following molecular rules has been generated, the impact of cellular rearrangements on cell viscoelasticity remains less understood. Thus, considering the density driven evolution of viscoelasticity caused by reduction of cell mobility could result in a powerful tool in order to address the contribution of cell jamming state transition in CCM and help to understand this important but still controversial topic. In addition, five viscoelastic states gained within three regimes: (1) convective regime, (2) conductive regime, and (3) damped-conductive regime was discussed based on the modeling consideration with special emphasis of jamming and unjamming states.

scholarly journals The role of the integrated stress response in keratinocyte migration

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jennifer Hartman ◽  
Miguel Barriera Diaz ◽  
Ronald C. Wek ◽  
Dan F. Spandau
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Stress Response ◽  
Protein Expression ◽  
Cell Lines ◽  
Actin Binding ◽  
Collective Cell Migration ◽  
Integrated Stress Response ◽  
Keratinocyte Migration

Background and Hypothesis: Cutaneous wound healing involves: hemostatic, inflammatory, proliferative, and tissue remodeling phases. Re-epithelialization can be modeled in vitro using human keratinocytes and artificial wounds. Previous work showed undifferentiated keratinocytes closing wounds in vitro using individual cell migration (ICM), whilst differentiated keratinocytes utilize collective cell migration (KCCM). Therefore, we hypothesize that ICM in vitro is equivalent to keratinocyte migration during squamous cell carcinoma metastasis in vivo and KCCM is a model for wound re-epithelialization. Furthermore, we hypothesize that the integrated stress response (ISR) is important in ICM and KCCM. The ISR is activated by environmental stresses that protein kinases (GCN2 and PERK) can detect and phosphorylate translation factor, eIF2a. Our goal is to define how the ISR, specifically GCN2 and PERK, influence keratinocyte migration. Methods: We will evaluate in vitro wound healing and kinetic variation in protein expression and cytoskeleton remodeling. We will utilize four keratinocyte cell lines, control human keratinocyte NTERTs, and CRISPR-derived gene knockouts of GCN2, PERK, and ISR effector gene ATF4. Quantitative analysis of wound healing is accomplished using an IncuCyte ZOOM instrument. Protein expression is measured via immunoblots following high density wounding. Cytoskeletal analyses was done by immunofluorescence. Results: Preliminary results show PERK-KO and GCN2-KO cells have reduced expression of F-actin. Immunoblots showed actin-binding protein, phospho-cofilin, at lower levels in PERK-KO and GCN2-KO cells than in NTERT cells. Wound healing assays showed differentiated keratinocytes healing faster than undifferentiated in all cells, except GCN2-KO. GCN2-KO cells healed significantly slower than other differentiated cells and undifferentiated GCN2-KO cells. Wound healing assays showed undifferentiated PERK-KO cells healing slower than other undifferentiated cell lines. Conclusion/Potential Impact: The results indicate PERK and GCN2 could be key components in ICM and CCM respectfully. GCN2 and PERK could thus be potential therapeutic targets to provide cost-effective therapeutics to enhance/inhibit keratinocyte migration.

scholarly journals Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migration in vivo

2021 ◽  
Author(s):  
Cristian L Marchant ◽  
Abdul N Malmi-Kakkada ◽  
Jaime A Espina ◽  
Elias H Barriga
Keyword(s):  
Cell Migration ◽  
Cancer Metastasis ◽  
Mechanical Response ◽  
Substrate Stiffness ◽  
Cell Stiffness ◽  
Collective Cell Migration ◽  
Force Microscopy ◽  
Atomic Force

Embryogenesis, tissue repair and cancer metastasis rely on collective cell migration (CCM). In vitro studies propose that migrating cells are stiffer when exposed to stiff substrates, known to allow CCM, but softer when plated in compliant non-permissive surfaces. Here, by combining in vivo atomic force microscopy (iAFM) and modelling we reveal that to collectively migrate in vivo, cells require to dynamically decrease their stiffness in response to the temporal stiffening of their native substrate. Moreover, molecular and mechanical perturbations of embryonic tissues uncover that this unexpected cell mechanical response is achieved by a new mechanosensitive pathway involving Piezo1-mediated microtubule deacetylation. Finally, lowering microtubule acetylation and consequently cell stiffness was sufficient to allow CCM in soft non-permissive substrates, suggesting that a fixed value of substrate stiffness is not as essential for CCM as it is reaching an optimal cell-to-substrate stiffness value. These in vivo insights on cell-to-substrate mechanical interplay have major implications to our re-interpretation of physiological and pathological contexts.

scholarly journals Emergence of single cell mechanical behavior and polarity within epithelial monolayers drives collective cell migration

2019 ◽  
Author(s):  
Shreyansh Jain ◽  
Victoire M.L. Cachoux ◽  
Gautham H.N.S. Narayana ◽  
Simon de Beco ◽  
Joseph D’Alessandro ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Large Scale ◽  
Cancer Metastasis ◽  
Cell Junctions ◽  
Collective Cell Migration ◽  
Convergent Extension ◽  
Cell Dynamics

The directed migration of cell collectives is essential in various physiological processes, such as epiboly, intestinal epithelial turnover, and convergent extension during morphogenesis as well as during pathological events like wound healing and cancer metastasis1,2. Collective cell migration leads to the emergence of coordinated movements over multiple cells. Our current understanding emphasizes that these movements are mainly driven by large-scale transmission of signals through adherens junctions3,4. In this study, we show that collective movements of epithelial cells can be triggered by polarity signals at the single cell level through the establishment of coordinated lamellipodial protrusions. We designed a minimalistic model system to generate one-dimensional epithelial trains confined in ring shaped patterns that recapitulate rotational movements observed in vitro in cellular monolayers and in vivo in genitalia or follicular cell rotation5–7. Using our system, we demonstrated that cells follow coordinated rotational movements after the establishment of directed Rac1-dependent polarity over the entire monolayer. Our experimental and numerical approaches show that the maintenance of coordinated migration requires the acquisition of a front-back polarity within each single cell but does not require the maintenance of cell-cell junctions. Taken together, these unexpected findings demonstrate that collective cell dynamics in closed environments as observed in multiple in vitro and in vivo situations5,6,8,9 can arise from single cell behavior through a sustained memory of cell polarity.

scholarly journals Roles of leader and follower cells in collective cell migration

2021 ◽  
Vol 32 (14) ◽  
pp. 1267-1272
Author(s):  
Lei Qin ◽  
Dazhi Yang ◽  
Weihong Yi ◽  
Huiling Cao ◽  
Guozhi Xiao
Keyword(s):  
Cell Migration ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Cell Movement ◽  
Special Focus ◽  
Collective Cell Migration ◽  
Force Transmission ◽  
Collective Movement

Collective cell migration is a widely observed phenomenon during animal development, tissue repair, and cancer metastasis. Considering its broad involvement in biological processes, it is essential to understand the basics behind the collective movement. Based on the topology of migrating populations, tissue-scale kinetics, called the “leader–follower” model, has been proposed for persistent directional collective movement. Extensive in vivo and in vitro studies reveal the characteristics of leader cells, as well as the special mechanisms leader cells employ for maintaining their positions in collective migration. However, follower cells have attracted increasing attention recently due to their important contributions to collective movement. In this Perspective, the current understanding of the molecular mechanisms behind the “leader–follower” model is reviewed with a special focus on the force transmission and diverse roles of leaders and followers during collective cell movement.

scholarly journals Hierarchical modeling of mechano-chemical dynamics of epithelial sheets across cells and tissue

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoshifumi Asakura ◽  
Yohei Kondo ◽  
Kazuhiro Aoki ◽  
Honda Naoki
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Continuum Model ◽  
Tissue Level ◽  
Chemical Signals ◽  
Cellular Level ◽  
Mathematical Framework ◽  
Collective Cell Migration ◽  
The Continuum ◽  
Cell Cell

AbstractCollective cell migration is a fundamental process in embryonic development and tissue homeostasis. This is a macroscopic population-level phenomenon that emerges across hierarchy from microscopic cell-cell interactions; however, the underlying mechanism remains unclear. Here, we addressed this issue by focusing on epithelial collective cell migration, driven by the mechanical force regulated by chemical signals of traveling ERK activation waves, observed in wound healing. We propose a hierarchical mathematical framework for understanding how cells are orchestrated through mechanochemical cell-cell interaction. In this framework, we mathematically transformed a particle-based model at the cellular level into a continuum model at the tissue level. The continuum model described relationships between cell migration and mechanochemical variables, namely, ERK activity gradients, cell density, and velocity field, which could be compared with live-cell imaging data. Through numerical simulations, the continuum model recapitulated the ERK wave-induced collective cell migration in wound healing. We also numerically confirmed a consistency between these two models. Thus, our hierarchical approach offers a new theoretical platform to reveal a causality between macroscopic tissue-level and microscopic cellular-level phenomena. Furthermore, our model is also capable of deriving a theoretical insight on both of mechanical and chemical signals, in the causality of tissue and cellular dynamics.

A Method for Quantitative Analysis of the Kinematics of Fibroblast Migration in a Monolayer Wound Model

2011 ◽  
Author(s):  
Gil Topman ◽  
Orna Sharabani-Yosef ◽  
Amit Gefen
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Wound Healing Assay ◽  
Complete Coverage ◽  
Time Intervals ◽  
Fibroblast Migration ◽  
Wound Model ◽  
Regular Time

A wound healing assay is simple but effective method to study cell migration in vitro. Cell migration in vitro was found to mimic migration in vivo to some extent [1,2]. In wound healing assays, a “wound” is created by either scraping or mechanically crushing cells in a monolayer, thereby forming a denuded area. Cells migrate into the denuded area to complete coverage, and thereby “heal” the wound. Micrographs at regular time intervals are captured during such experiments for analysis of the process of migration.

scholarly journals Self-organized cell migration across scales – from single cell movement to tissue formation

Development ◽  
2021 ◽  
Vol 148 (7) ◽  
pp. dev191767
Author(s):  
Jessica Stock ◽  
Andrea Pauli
Keyword(s):  
Cell Migration ◽  
Multiple Scales ◽  
Single Cells ◽  
Cell Movement ◽  
Biological Response ◽  
Collective Cell Migration ◽  
Theoretical Concepts ◽  
Self Organizing

ABSTRACTSelf-organization is a key feature of many biological and developmental processes, including cell migration. Although cell migration has traditionally been viewed as a biological response to extrinsic signals, advances within the past two decades have highlighted the importance of intrinsic self-organizing properties to direct cell migration on multiple scales. In this Review, we will explore self-organizing mechanisms that lay the foundation for both single and collective cell migration. Based on in vitro and in vivo examples, we will discuss theoretical concepts that underlie the persistent migration of single cells in the absence of directional guidance cues, and the formation of an autonomous cell collective that drives coordinated migration. Finally, we highlight the general implications of self-organizing principles guiding cell migration for biological and medical research.

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