Topological defects in epithelia govern cell death and extrusion.

Abstract

Epithelia remove excess cells through extrusion, and prevent accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signaling1, oncogenic transformation2,3, and overcrowding of cells4–6. Despite the important links of cell extrusion to developmental7, homeostatic5 and pathological processes2,8,9 such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. Here, we show that apoptotic cell extrusion is provoked by singularities in cell alignments9,10 in the form of comet-like topological defects. We find a universal correlation between the extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. We model the epithelium as an active nematic liquid crystal and compare numerical simulations to strain rate and stress measurements within cell monolayers. The results confirm the active nematic nature of epithelia for the first time, and demonstrate that defect-induced isotropic stresses are the primary precursor of mechanotransductive responses in cells such as YAP (Yes-associated protein) transcription factor activity11, caspase-3 mediated cell death, and extrusions. Importantly, the defect-driven extrusion mechanism depends on intercellular junctions, since the weakening of cell-cell interactions in α-catenin knockdown (α-catKD) monolayer reduces the defect size and increases both the number of defects and extrusion rates, as also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact-printing of patterned monolayers. Together we propose a novel mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This new finding has important implications in predicting extrusion hotspots and dynamics in vivo, with potential applications to tissue regeneration and metastasis suppression. Moreover, we anticipate that the analogy between the epithelium and active nematic liquid crystals will trigger further investigations of the link between cellular processes and the material properties of epithelia.