Enhanced substrate stress relaxation promotes filopodia-mediated cell migration

Adebowale, Kolade; Gong, Zhiyuan; Hou, Jay; Wisdom, Katrina M.; Garbett, Damien; Lee, Hong pyo; Nam, Sungmin; Meyer, Tobias; Odde, David J.; Shenoy, Vivek B.; Chaudhuri, Ovijit

doi:10.1038/s41563-021-00981-w

Cited by 141 publications

(139 citation statements)

References 53 publications

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“…This result confirmed that lowering cell stiffness is sufficient for cells to migrate regardless the mechanical nature of their environment. Further studying these new observations can have deep implications for our understanding of processes such as cancer cell migration as recent data suggest that these cells often migrate across soft viscoelastic native tissues 38 , as the ones we report here.…”

Section: Discussionsupporting

confidence: 60%

Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migrationin vivo

Marchant

Malmi-Kakkada

Espina

et al. 2021

Preprint

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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.

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Section: Discussionsupporting

confidence: 60%

Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migrationin vivo

Marchant

Malmi-Kakkada

Espina

et al. 2021

Preprint

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“…25 Third, studies of cell behavior on 2-D viscoelastic substrates have reported increased migration speed on substrates with faster relaxation times. 13 However, cells were also more circular on faster-relaxing substrates and formed only weak, nascent adhesions that do not support strong tractions that are needed for confined 3-D migration. 22,26 Hence, the effect of stress relaxation speed on cell migration in a 3-D environment may depend on the material’s steric hindrance, which in turn depends on the elasticity, porosity, and - as argued above - on the amplitude of stress relaxation.…”

Section: Discussionmentioning

confidence: 97%

“…The biological effects of a more pronounced stress relaxation have been explained by a greater malleability of the matrix, while the effects of a faster stress relaxation have been explained by an enhanced integrin clustering and adhesion through the formation of integrin-associated catch bonds. 12,13…”

Section: Introductionmentioning

confidence: 99%

Stress relaxation amplitude of hydrogels determines migration, proliferation, and morphology of cells in 3-D

Hazur

Endrizzi

Schubert³

et al. 2021

Preprint

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The viscoelastic behavior of hydrogel matrices sensitively influences the cell behavior in 3D culture and biofabricated tissue model systems. Previous reports have demonstrated that cells tend to adhere, spread, migrate and proliferate better in hydrogels with pronounced stress relaxation. However, it is currently unknown if cells respond more sensitively to the amplitude of stress relaxation, or to the relaxation time constant. To test this, we compare the behavior of fibroblasts cultured for up to 10 days in alginate and oxidized alginate hydrogels with similar Young’s moduli but diverging stress relaxation behavior. We find that fibroblasts elongate, migrate and proliferate better in hydrogels that display a higher stress relaxation amplitude. By contrast, the cells’ response to the relaxation time constant was less pronounced and less consistent. Together, these data suggest that it is foremost the stress relaxation amplitude of the matrix that determines the ability of cells to locally penetrate and remodel the matrix, which subsequently leads to better spreading, faster migration, and higher cell proliferation. We conclude that the stress relaxation amplitude is a central design parameter for optimizing cell behavior in 3-D hydrogels.

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“…[43][44][45] Recent observations in vitro and in vivo have further challenged our current view of the function of filopodia in migrating cells. [4,46] Adebowale and colleagues found that filopodial protrusions mediate migration of cultured human cancer cells on soft, fast-relaxing substrates suggesting that filopodia-based migration may play a key role in cancer metastasis in physiologically relevant 3D environments [46] (Figure 1A). Recent livecell-imaging experiments further showed that filopodia play not only an important role in cancer progression, but also in collective migration of testis nascent myotubes during Drosophila development (Figure 1D).…”

Section: Filopodia-based Cell Migrationmentioning

confidence: 99%

“…Depending on the substrate, single cells can also use filopodia-based migration mode. [46] (B) In 3D, there are varieties of both, lamellipodia-based migration and bleb-based motility. Lobopodia are protrusions that share traits of both.…”

Section: Filopodia-based Cell Migrationmentioning

confidence: 99%

Collective cell migration driven by filopodia—New insights from the social behavior of myotubes

Bischoff

Bogdan

2021

BioEssays

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Collective migration is a key process that is critical during development, as well as in physiological and pathophysiological processes including tissue repair, wound healing and cancer. Studies in genetic model organisms have made important contributions to our current understanding of the mechanisms that shape cells into different tissues during morphogenesis. Recent advances in high-resolution and live-cell-imaging techniques provided new insights into the social behavior of cells based on careful visual observations within the context of a living tissue. In this review, we will compare Drosophila testis nascent myotube migration with established in vivo model systems, elucidate similarities, new features and principles in collective cell migration.

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Enhanced substrate stress relaxation promotes filopodia-mediated cell migration

Cited by 141 publications

References 53 publications

Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migrationin vivo

Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migrationin vivo

Stress relaxation amplitude of hydrogels determines migration, proliferation, and morphology of cells in 3-D

Collective cell migration driven by filopodia—New insights from the social behavior of myotubes

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