Mechanical interactions among followers determine the emergence of leaders in migrating epithelial cell collectives

Abstract

Regulating the emergence of leaders is a central aspect of collective cell migration, but the underlying mechanisms remain ambiguous. Here we show that the selective emergence of leader cells at the epithelial wound-margin depends on the dynamics of the follower cells and is spatially limited by the length-scale of collective force transduction. Owing to the dynamic heterogeneity of the monolayer, cells behind the prospective leaders manifest locally increased traction and monolayer stresses much before these leaders display any phenotypic traits. Followers, in turn, pull on the future leaders to elect them to their fate. Once formed, the territory of a leader can extend only to the length up-to which forces are correlated, which is similar to the length up-to which leader cells can transmit forces. These findings provide mechanobiological insight into the hierarchy in cell collectives during epithelial wound healing.

Motility-limited aggregation of mammary epithelial cells into fractal-like clusters

“…These leader cells were mechanically coupled with a group of follower cells and exhibited highly correlated directional motion, which could be explained by sustained polarization due to cell-cell junctions with neighbors (14), but also a universal coupling of cell speed and persistence driven by actin retrograde flow (50) or EMT (2). Moreover, the number of leader cells increased with cluster size, with an average separation of ∼250 µm between leaders, comparable to previously reported values for straight migration fronts (11,17). The highly curved periphery of these fractallike clusters likely enhances leader cell formation relative to straight fronts, in good agreement with previous theoretical models that postulate a curvature-dependent motility (10,15), as well as experiments with micropatterned fronts (9,12,13,15).…”

“…Such behaviors are observed with clusters of epithelial cells in vitro, which "scatter" individually upon addition of epidermal growth factor (EGF) (3,4) or hepatocyte growth factor (HGF) (5)(6)(7). Similarly, a "partial" EMT is associated with leader cells that exhibit enhanced motility but retain some cell-cell contacts for mechanical guidance of their followers (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Instead, a reverse mesenchymal-epithelial transition (MET) can occur when mesenchymal cells condense and differentiate into a compact epithelial tissue, associated with skeletal development in vivo (18).…”

Curling of epithelial monolayers reveals coupling between active bending and tissue tension

“…Although each of these mechanisms in isolation can give rise to folding, theoretical and experimental insights suggest that variations of in-plane stresses at the tissue-scale can act in parallel to apical or basal constrictions to define the three-dimensional shape of epithelia (12)(13)(14). Yet, in contrast to the mechanical properties and active forces generated by epithelial monolayers within the plane (11,(15)(16)(17)(18)(19)(20), outof-plane forces and mechanical properties of epithelia (active torques and bending modulus) have not been characterized. Consequently, the relative magnitudes of forces acting inplane and out-of-plane remain unknown, making the contribution of out-of-plane stresses to morphogenesis challenging to assess.…”

Surface Immobilized E‐Cadherin Mimetic Peptide Regulates the Adhesion and Clustering of Epithelial Cells

“…The cells adhere more stably and thus migrated less on RH surfaces than on RS surfaces. By contrast, the mobility of the cells in clusters was mostly driven by the tension generated by neighbor cells . As the cell–cell interactions decreased on RH surfaces, the clusters were unstable and cells tended to migrate.…”

“…Therefore, the cytoskeletal filaments of each cell are linked to an extensive transcellular network by way of cadherin‐based adhesion at the cell–cell interface, thus allowing force transmission across the interior of cells . In addition, this connection also activates cadherin‐mediated downstream signaling pathways to regulate a variety of cell behaviors like polarity signal propagation, collective cell migration, and cell differentiation …”