Cell clusters softening triggers collective cell migration in vivo

Abstract

Embryogenesis, tissue repair and cancer metastasis rely on collective cell migration. In vitro studies propose that cells are stiffer while migrating in stiff substrates, but softer when plated in compliant surfaces which are typically considered as non-permissive for migration. Here we show that cells within clusters from embryonic tissue dynamically decrease their stiffness in response to the temporal stiffening of their native substrate to initiate collective cell migration. Molecular and mechanical perturbations of embryonic tissues reveal that this unexpected mechanical response involves a mechanosensitive pathway relying on Piezo1-mediated microtubule deacetylation. We further show that decreasing microtubule acetylation and consequently cluster stiffness is sufficient to trigger collective cell migration in soft non-permissive substrates. This suggests that reaching an optimal cluster-to-substrate stiffness ratio is essential to trigger the onset of this collective process. Overall, these in vivo findings challenge the current understanding of collective cell migration and its physiological and pathological roles.

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

“…( 2018 )). Interestingly, recent studies found that PIEZO1 inhibition suppresses collective migration and results in a decrease in the directionality of migrating Xenopus neural crest cells ( Canales Coutiño and Mayor ( 2021 ); Marchant et al . ( 2022 )).…”

Reconfigurable scaffolds for adaptive tissue regeneration

“…Though the feasibility of altering the morphology and focal adhesion of individual cell through programming the reconfigurations of scaffold micro-structures has been widely investigated and the potential outcomes of evoking the cascade of gene expression via mechanotransduction could be predicted, it is still difficult to assume the similar effects on the collective behaviours and functions of the amounts of cells involving complicated cell-cell interactions. 120,121 By using SMPs and micro-fabrication/micro-embossing methods, a variety of scaffolds with temperature-actuated reconfigurable microstructures, enabling reconfigurations either from micro-/nano-topographies to flat or in a reverse way, have been developed and employed to investigate the mechanotransduction of dynamic topographical cues on collective cellular behaviours and functions. 28,[122][123][124][125] For different cell models such as NIH-3T3 fibroblast cell lines, 28,122 primary mouse embryonic fibroblasts, 122 and human-derived stem cells, 123,124 the reconfigurations of scaffold micro-structures could always cause the switches of cellular shapes and reorientations of cytoskeletons for a large number of cells.…”

Emerging concepts on the mechanical interplay between migrating cells and microenvironment in vivo

“…As described above, an increase in mesoderm stiffness is required to induce NC EMT and migration ( Barriga et al, 2018 ). However, recent work has shown that pre-migratory NC cells respond to the increased substrate stiffness by changing their mechanical properties ( Marchant et al, 2022 ). In this mechanism, NC cells activate the mechanosensitive Piezo1 channel, causing NC cells to reduce microtubule (MT) acetylation ( Figure 2H ).…”