Bidirectional multiciliated cell extrusion is controlled by Notch driven basal extrusion and Piezo 1 driven apical extrusion

Abstract

Xenopus embryos are covered with a complex epithelium containing numerous multiciliated cells (MCCs). During late stage development there is a dramatic remodeling of the epithelium that involves the complete loss of MCCs. Cell extrusion is a well-characterized process for driving cell loss while maintaining epithelial barrier function. Normal cell extrusion is typically unidirectional whereas bidirectional extrusion is often associated with disease (e.g. cancer). We describe two distinct mechanisms for MCC extrusion, a basal extrusion driven by Notch signaling and an apical extrusion driven by Piezo1. Early in the process there is a strong bias towards basal extrusion, but as development continues there is a shift towards apical extrusion. Importantly, receptivity to the Notch signal is age-dependent and governed by the maintenance of the MCC transcriptional program such that extension of this program is protective against cell loss. In contrast, later apical extrusion is regulated by Piezo 1 such that premature activation of Piezo 1 leads to early extrusion while blocking Piezo 1 leads to MCC maintenance. Distinct mechanisms for MCC loss underlie the importance of their removal during epithelial remodeling.

Piezo1 in Digestive System Function and Dysfunction

“…This dual role of Piezo1 activation may correlate with the dose-response curve of Yoda1 administration [ 85 , 86 ]. Moreover, one potential apoptosis-associated mechanism is that Piezo1 activation induces the extrusion of epithelial cells, different from the pro-proliferation role of Piezo1 as well [ 87 , 88 ]. Given that Piezo mechanosensitivity is multifactorial [ 89 ], precise cellular effects of Piezo1 requires accurate intervention such as optogenetics to be clarified in specific conditions [ 90 ].…”

“…The integrity of intestinal epithelial barrier depends on stable cell turnover and constant cell numbers [ 152 ]. When epithelial cells crowds and cytoskeleton contracts, Piezo1 is activated to promote the apical extrusion; while mechanosensitive Piezo1 disruption inhibits extrusion and forms epithelial cell masses [ 87 , 88 ], resulting in imbalanced cell numbers and impaired epithelial barrier. Tight junction seals the epithelial and endothelial monolayers, and it is formed by associated protein such as claudins, occludin, ZO-1.…”