Airway epithelial homeostasis and planar cell polarity signaling depend on multiciliated cell differentiation

Abstract

Motile airway cilia that propel contaminants out of the lung are oriented in a common direction by planar cell polarity (PCP) signaling, which localizes PCP protein complexes to opposite cell sides throughout the epithelium to orient cytoskeletal remodeling. In airway epithelia, PCP is determined in a 2-phase process. First, cell-cell communication via PCP complexes polarizes all cells with respect to the proximal-distal tissue axis. Second, during ciliogenesis, multiciliated cells (MCCs) undergo cytoskeletal remodeling to orient their cilia in the proximal direction. The second phase not only directs cilium polarization, but also consolidates polarization across the epithelium. Here, we demonstrate that in airway epithelia, PCP depends on MCC differentiation. PCP mutant epithelia have misaligned cilia, and also display defective barrier function and regeneration, indicating that PCP regulates multiple aspects of airway epithelial homeostasis. In humans, MCCs are often sparse in chronic inflammatory diseases, and these airways exhibit PCP dysfunction. The presence of insufficient MCCs impairs mucociliary clearance in part by disrupting PCP-driven polarization of the epithelium. Consistent with defective PCP, barrier function and regeneration are also disrupted. Pharmacological stimulation of MCC differentiation restores PCP and reverses these defects, suggesting its potential for broad therapeutic benefit in chronic inflammatory disease.

Active mucus-cilia hydrodynamic coupling drives self-organisation of human bronchial epithelium

“…1a). The pseudo-stratified tissue consists of basal cells, goblet cells and ciliated cells each carrying 200-300 active cilia gathered in bundles on the apical surface 13 . After cellular differentiation, the tissue exhibits the characteristics of the bronchial epithelium 14 such as active cilia beating at a frequency of about 8-10 Hz and the production and transport of mucus on the epithelium surface.…”

Lung organoids: current uses and future promise

“…There are many potential questions that could be addressed using such a resource. For example, airway epithelial cells could be produced from iPSCs derived from patients with chronic asthma or CF to test the idea that epigenetic changes in the progenitors affect their self-renewal and differentiation capacity Vladar et al, 2016). CF iPSC-derived lung organoids could also provide a reliable and reproducible source of CF mutant cells for screening drugs that compensate for, or correct, patient-specific mutations (Wong et al, 2012).…”

Noncanonical Wnt planar cell polarity signaling in lung development and disease

“…The developmental PCP program that first orients airway cilia for MCC remains active postnatally and in the adult airway epithelium [12,60]. This is in marked contrast with other planar polarized tissues like the cochlear and kidney tubule epithelia [58,71], where PCP is down-regulated after its developmental functions.…”

“…Finally, PCP has also been shown to have nonciliated cell functions. The loss of core PCP components leads to diminished airway epithelial barrier function [12]. Adherens junctional integrity is critical to barrier capacity, and the loss of Vangl2 at the adherens junctions has been shown to disrupt E-cadherin, its chief structural and functional component, in renal epithelial cells [73].…”

“…PCP is best known as a developmental regulator of polarized tissue morphogenesis involved in the hair follicle and cochlear hair cell orientation and convergent extension during neural tube closure [9][10][11]. However, it also carries out homeostatic roles in adult organs, including the lung [12,13] and is accordingly involved in diseases affecting these tissues [14]. The most completely elucidated PCP signaling mechanism is for its namesake processthe polarization of cells along the proximal-distal plane of an epithelial sheet, orthogonal to their apical-basal axis ( Figure 1B).…”