Flexibility sustains epithelial tissue homeostasis

Abstract

Epithelia surround our bodies and line most of our organs. Intrinsic homeostatic mechanisms replenish and repair these tissues in the face of wear and tear, wounds, and even the presence of accumulating mutations. Recent advances in cell biology, genetics, and live-imaging techniques have revealed that epithelial homeostasis represents an intrinsically flexible process at the level of individual epithelial cells. This homeostatic flexibility has important implications for how we think about the more dramatic cell plasticity that is frequently thought to be associated with pathological settings. In this review, we will focus on key emerging mechanisms and processes of epithelial homeostasis and elaborate on the known molecular mechanisms of epithelial cell interactions to illuminate how epithelia are maintained throughout an organism's lifetime.

Figure 1.. Cellular neighborhoods impact epithelial fate decisions.

During normal epithelial turnover in Drosophila and mammalian intestinal epithelium, mechanical crowding from cell proliferation activates the stretch-responsive Piezo1 channel to trigger the extrusion of live cells, which later die by apoptosis. (A) New epithelial cells in the intestinal epithelium migrate and differentiate along the villus and in response to crowding stress, and cells extrude at the villus tip to maintain homeostatic cell numbers. (B) An increase in cellular crowding forces promotes basal extrusion in Drosophila intestinal epithelium. Mechanical forces from cell stretching can also activate stretch-activated Piezo1 channels and increase cytosolic calcium. A calcium influx can trigger two different outcomes: proliferation through calcium-dependent activation of ERK and differentiation towards the enteroendocrine lineage through calcium-regulation of Notch signaling. Additionally, healthy cells inhibit intestinal epithelial cell division through E-cadherin (E-cad), which prevents the secretion of mitogenic epidermal growth factors (EGFs). Individual apoptotic cells promote division by the loss of E-cad, which releases β-catenin and p120-catenin to induce rhomboid (rho). Induction of rho triggers the activation of the EGF receptor (EGFR).

Figure 2.. Flexible homeostatic mechanisms maintain epithelial homeostasis across time and in face of mutational insults.

In many epithelial tissues, flexible homeostatic mechanisms are in place to maintain these tissues in a state of functional normalcy through the development or acquisition of mutational insults. In embryonic mammalian skin epidermis (left), a single basal layer of epithelial cells adheres to an underlying basement membrane. In this layer, crowding and proliferation of cells lead to apical extrusion from the basal layer. In adult mammalian skin epidermis (middle), a single basal layer of epithelial cells underlies suprabasal layers of differentiated cells. In this case, differentiation of a cell, which causes it to leave the basal layer, is then followed directly by the division of an adjacent neighboring cell. After mutation (right), flexible homeostatic mechanisms can lead mutant cells to be actively eliminated out of the tissue or even incorporated into the normal homeostatic program to return the tissue to overall normalcy.