Publications

Growing evidence suggests that the physical properties of the cellular microenvironment influence cell migration. However, it is not currently understood how active physical remodelling by cells affects migration dynamics. Here we report that cell clusters seeded on deformable collagen-I networks display persistent collective migration despite not showing any apparent intrinsic polarity. Clusters generate transient gradients in collagen density and alignment due to viscoelastic relaxation of the collagen networks. Combining theory and experiments, we show that crosslinking collagen networks or reducing cell cluster size results in reduced network deformation, shorter viscoelastic relaxation time and smaller gradients, leading to lower migration persistence. Traction force and Brillouin microscopy reveal asymmetries in force distributions and collagen stiffness during migration, providing evidence of mechanical cross-talk between cells and their substrate during migration. This physical model provides a mechanism for self-generated directional migration on viscoelastic substrates in the absence of internal biochemical polarity cues.; Cell clusters mechanically reorganize viscoelastic collagen networks, resulting in transient gradients in collagen density, alignment and stiffness that promote spontaneous persistent migration.

JTD Keywords: Cell-migration, Design, Invasion, Limits, Mechanics, Microscopy, Morphogenesis, Motility, Rear, Rigidity

During collective migration of epithelial cells, the migration direction is aligned over a 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 yields long-distance transmission of guidance cues. Mechanical stretch activates ERK through epidermal growth factor receptor (EGFR) activation, and ERK activation triggers cell contraction. The contraction of the activated cell pulls neighboring cells, evoking another round of ERK activation and contraction in the neighbors. Furthermore, anisotropic contraction based on front-rear polarization guarantees unidirectional propagation of ERK activation, 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.

JTD Keywords: Collective cell migration, EGFR, ERK/MAPK, FRET, Front-rear polarity, Intercellular signal transfer, Mathematical model, Mechanochemical feedback, Mechanotransduction, wave propagation

Transmission electron microscopy, temperature-modulated differential scanning calorimetry, and broadband dielectric spectroscopy were employed to characterize ternary nanocomposites consisting of carboxylated carbon nanotubes (CNT) dispersed in a blend of two immiscible polymers, poly(L,lactide) (PLLA) and thermoplastic polyurethane (TPU). The nanocomposite blends were obtained by melt-compounding of PLLA and TPU in the presence of 0.2 wt-% CNT, either in the presence or absence of a Joncryl® ADR chain extender for PLLA, leading to reactive and non-reactive melt mixed samples. In both cases, the binary PLLA/TPU blend is characterized by phase separation into submicron TPU droplets dispersed in the PLLA matrix, and displays two separate glass transition temperatures. The carbon nanotubes are present either inside the TPU phase (samples obtained without chain extender), or at their boundaries (reactive-melt mixed samples). The effect of the sub-micron confinement of the TPU component is to decrease the cooperativity length of the primary segmental relaxation of this polymer, which is accentuated by the presence of the CNT fillers. Depending on the type of sample, five or six distinct relaxations are observed by means of dielectric spectroscopy, which we are able to assign to different dielectric phenomena. Our dielectric data show that the CNT fillers do not contribute directly to the long-range charge transport in the nanocomposite blends, consistent with the nanocomposites morphology, but rather result in a shift of the Maxwell-Wagner-Sillars space-charge frequency associated with charge accumulation at the PLLA/TPU boundary. Such shift testifies to a selective conductivity enhancement of the TPU phase due to the filler.

JTD Keywords: Conductivity enhancement, Cooperatively rearranging region, Dielectric spectroscopy, Glass transition, Maxwell-Wagner-Sillars relaxation, Nanofiller