The role of single-cell mechanical behaviour and polarity in driving collective cell migration

Jain, Shreyansh; Cachoux, Victoire M L; Narayana, Gautham Hari Narayana Sankara; Beco, Simon de; D’Alessandro, Joseph; Cellerin, Victor; Chen, Tianchi; Heuzé, Mélina L.; Marcq, Philippe; Mège, René-Marc; Kabla, Alexandre; Lim, Chwee Teck; Ladoux, Benoît

doi:10.1038/s41567-020-0875-z

Cited by 139 publications

(170 citation statements)

References 57 publications

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“…Before injury, GFP-CAAX/MRLC-mCherry cells displayed both a Myosin IIenriched cortex that was most evident at the zonula adherens (ZA), as well as dynamic lamellipodial protrusions that appeared to be randomly oriented around the cell periphery ( Fig 1B), as has been reported previously in epithelia [6,7]. Within 1-2 min of inducing apoptosis, lamellipodia extended from the neighbour cells underneath the injured cells ( Fig 1B-D, Supplementary Movie 2).…”

supporting

confidence: 69%

A unified view of neighbour cell engagement during apoptotic cell extrusion

Duszyc

Gómez

Lagendijk

et al. 2020

Preprint

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Epithelia must eliminate apoptotic cells to preserve tissue barriers and prevent inflammation [1]. Several different mechanisms exist for apoptotic clearance, including efferocytosis [2, 3] and apical extrusion [4, 5]. We found that extrusion was the first-line response to apoptosis in cultured monolayers and in zebrafish epidermis. During extrusion, the apoptotic cell elicited active lamellipodial protrusions and assembly of a contractile extrusion ring in its neighbours. Depleting E-cadherin compromised both the contractile ring and extrusion, implying that a cadherin-dependent pathway allows apoptotic cells to engage their neighbours for extrusion. We identify RhoA as the cadherin-dependent signal in the neighbour cells and show that it is activated in response to contractile tension from the apoptotic cell. This mechanical stimulus is conveyed by a Myosin VI-dependent mechanotransduction pathway that is necessary both for extrusion and to preserve the epithelial barrier when apoptosis was stimulated. Earlier studies suggested that release of sphingosine-1-phosphate (S1P) from apoptotic cells might define where RhoA was activated. However, we found that although S1P is necessary for extrusion, its contribution does not require a localized source of S1P in the epithelium. We therefore propose a unified view of how RhoA is stimulated to engage neighbour cells for apoptotic extrusion. Here, tension-sensitive mechanotransduction is the proximate mechanism that activates RhoA specifically in the immediate neighbours of apoptotic cells, but this also must be primed by S1P in the tissue environment. Together, these elements provide a coincidence detection system that confers robustness on the extrusion response.

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supporting

confidence: 69%

A unified view of neighbour cell engagement during apoptotic cell extrusion

Duszyc

Gómez

Lagendijk

et al. 2020

Preprint

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“…In addition, the model makes predictions that can motivate future experimental exploration. Finally, having a model for singlecell motility can serve as the basis for the description of collective cell migration [40], which goes beyond treatments of the cells as simplified self-propelled particles. diffusion coefficient of different proteins in the cell [27], is estimated by…”

Section: Discussionmentioning

confidence: 99%

One-dimensional cell motility patterns

Ron

Monzo

Gauthier

et al. 2020

Phys. Rev. Research

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During migration, cells exhibit a rich variety of seemingly random migration patterns, which makes unraveling the underlying mechanisms that control cell migration a difficult challenge. For efficient migration, cells require a mechanism for polarization, so that traction forces are produced in the direction of motion, while adhesion is released to allow forward migration. To simplify the study of this process, cells have been studied when placed along one-dimensional tracks, where single cells exhibit both smooth and stick-slip migration modes. The stick-slip motility mode is characterized by protrusive motion at the cell front, coupled with a slow elongation of the cell, which is followed by a rapid retraction of the cell rear. In this study, we explore a minimal physical model that couples the force applied on the adhesion bonds to the length variations of the cell and to the traction forces applied by the polarized actin retrograde flow. We show that the rich spectrum of cell migration patterns emerges from this model as different deterministic dynamical phases. This result suggests a source for the large cell-tocell variability (CCV) in cell migration patterns observed in single cells over time and within cell populations: fluctuations in the cellular components, such as adhesion strength or polymerization activity, can shift the cells from one migration mode to another, due to crossing the dynamical phase transition lines. Temporal noise is shown to drive random changes in the cellular polarization direction, which is enhanced during the stick-slip migration mode. The model contains an emergent critical length for cell polarization, whereby cells that retract below this length loose polarity, and are prone to making direction changes in migration. These results offer a new framework to explain experimental observations of migrating cells, resulting from noisy switching between underlying deterministic migration modes.

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“…2b). We validated the presence of lamellipodia by looking at cell extrusions in mosaic cultures of WT and MDCK expressing YFP-tagged p21 binding domain (PBD), a fluorescent biosensor of active Rac1 and Cdc42, [18,19] for both laser-induced cell death extrusions ( Supplementary Fig. 1a, b) and naturally-occurring extrusions ( Supplementary Fig.…”

Section: Extrusion Depends On Dual-mechanism Which Combines Lamellipomentioning

confidence: 99%

Adhesion-mediated heterogeneous actin organization governs apoptotic cell extrusion

Rupprecht

Mège

et al. 2020

Preprint

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Apoptotic extrusion is crucial in maintaining epithelial homeostasis and has implications in diseases of epithelial tissues. Current literature supports that epithelia respond to extrusion to maintain their integrity by the formation of a supracellular actomyosin ring (purse-string) in the neighbors that encompasses the dying cells. However, little is known about whether other types of actin structures could contribute to extrusion as well as how forces generated by mechanosensitive proteins in the cells are integrated. Here, we found that during extrusion, a heterogeneous actin network composed of lamellipodia protrusions and discontinuous actomyosin cables, was reorganized in the neighboring cells and was the main factor driving extrusion forwards. The early presence of basal lamellipodia protrusion participated both in basal sealing of the extrusion site and in orienting the actomyosin purse-string at the later stage of extrusion. These sequential events are essential in ensuring a successful extrusion in apicobasal direction. The co-existence of these two mechanisms is determined by the interplay between the cell-cell and cell-substrate adhesions. A theoretical model integrates the role of these cellular mechanosensitive components to explain why a dual-mode mechanism, which combined lamellipodia protrusion and purse-string contractility, leads to more efficient extrusion than a single-mode mechanism. We anticipate that our approach will be useful to provide mechanistic insight into epithelial homeostasis, morphogenetic events and tumorigenesis.

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The role of single-cell mechanical behaviour and polarity in driving collective cell migration

Cited by 139 publications

References 57 publications

A unified view of neighbour cell engagement during apoptotic cell extrusion

A unified view of neighbour cell engagement during apoptotic cell extrusion

One-dimensional cell motility patterns

Adhesion-mediated heterogeneous actin organization governs apoptotic cell extrusion

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