ERK-mediated mechanochemical waves direct collective cell polarization

Abstract

During collective migration of epithelial cells, the migration direction is aligned over a large, tissue-scale expanse. Although the collective cell migration is known to be directed by mechanical forces transmitted via cell-cell junctions, it remains elusive how the intercellular force transmission is coordinated with intracellular biochemical signaling to achieve collective movements. Here we show that intercellular coupling of extracellular signal-regulated kinase (ERK)-mediated mechanochemical feedback in individual cells yields long-distance transmission of guidance cues. Mechanical stretch activates ERK through epidermal growth factor receptor (EGFR) activation, and the ERK activation triggers cell contraction. In addition, the contraction of the activated cell pulls neighboring cells via cell-cell junctions, evoking another round of ERK activation and contraction in the neighbors. Furthermore, anisotropic contraction based on front-rear cell polarization guarantees unidirectional propagation of ERK activation waves, and in turn, the ERK activation waves direct multicellular alignment of the polarity, leading to long-range ordered migration. Our findings reveal that mechanical forces mediate intercellular signaling underlying sustained transmission of guidance cues for collective cell migration.

Robustness of epithelial sealing is an emerging property of local ERK feedbacks driven by cell elimination

“…We exclude the contribution of calcium signaling or an active secretion of the ligand from the dying cell, while laser induced wound healing was sufficient to promote neighbouring cell stretching and ERK activation. Other recent works have characterized the rapid effect of cell stretching on ERK activation 20,21 , which was recently shown to also rely on EGFR 22 . Further work characterising the molecular mechanism of cell deformation sensing by ERK will be required to fully test the contribution of mechanics in extrusion-induced ERK activation.…”

Theory of mechano-chemical patterning and optimal migration in cell monolayers

“…with the time scale ⌧ E indicating how quickly ERK reacts to mechanical deformations, and determining the strength of coupling between cell length and ERK levels. Live-measurements of ERK activity demonstrate that stretching MDCK monolayers results in an activation of ERK [11], suggesting that > 0 in this system (see SI Text Section I D 1 for further details).…”

“…Finally, given the reported mechano-sensitivity of ERK and its dependency on cell length (@ x r, inversely proportional to cell density) [11], a minimal equation for ERK activity, again assuming generic first-order couplings, reads…”

“…Imaging monolayer movements together with ERK/MAPK activity has for instance revealed that the previously observed spatio-temporal waves in cell density are accompanied by corresponding waves of ERK activity (with ERK activity locally anti-correlated to cell density) [10]. Strikingly, such ERK waves were also observed in vivo during wound healing in mouse skin [25], and shown to be crucial for robust directional migration in response to a wound in vitro [11]. Given that the ERK/MAPK pathway is a central signalling platform, able to integrate and modulate mechanical forces [10,11,[26][27][28], these experiments raise the intriguing possibility that mutual mechano-chemical feedback loops control the behaviour [5,29,30], although this remains to be systematically and theoretically explored in monolayers.…”

“…However, how mechanical and chemical signaling are integrated at the cellular level to give rise to such collective behaviors remains unclear. We address this by focusing on the highly conserved phenomenon of spatio-temporal waves of density [2,[4][5][6][7][8] and ERK/MAPK activation [9][10][11], which appear both in vitro and in vivo during collective cell migration and wound healing. First, we propose a biophysical theory, backed by mechanical and optogenetic perturbation experiments, showing that patterns can be quantitatively explained by a mechano-chemical coupling between three-dimensional active cellular tensions and the mechano-sensitive ERK/MAPK pathway.…”