Airway epithelial basal cells are known to be critical for regenerating injured epithelium and maintaining tissue homeostasis. Recent evidence suggests that the α7 nicotinic acetylcholine receptor (nAChR), which is highly permeable to Ca
2+, is involved in lung morphogenesis. Here, we have investigated the potential role of the α7 nAChR in the regulation of airway epithelial basal cell proliferation and the differentiation of the human airway epithelium.
In vivo during fetal development and
in vitro during the regeneration of the human airway epithelium, α7 nAChR expression coincides with epithelium differentiation. Inactivating α7 nAChR function
in vitro increases cell proliferation during the initial steps of the epithelium regeneration, leading to epithelial alterations such as basal cell hyperplasia and squamous metaplasia, remodeling observed in many bronchopulmonary diseases. The regeneration of the airway epithelium after injury in α7
−/− mice is delayed and characterized by a transient hyperplasia of basal cells. Moreover, 1-year-old α7
−/− mice more frequently present basal cells hyperplasia. Modulating nAChR function or expression shows that only α7 nAChR, as opposed to heteropentameric α
xβ
y nAChRs, controls the proliferation of human airway epithelial basal cells. These findings suggest that α7 nAChR is a key regulator of the plasticity of the human airway epithelium by controlling basal cell proliferation and differentiation pathway and is involved in airway remodeling during bronchopulmonary diseases.The respiratory epithelium, which is constantly exposed to airborne pollutants, is frequently injured, which results in altered epithelial functions. To restore these functions, the respiratory epithelium must undergo rapid repair via epithelial cell spreading and migration and regenerate its structure via basal cell proliferation and differentiation.
1 These processes are tightly controlled to restore the pseudostratified architecture of the normal mucociliary epithelium. However, in most respiratory diseases, alterations of the regeneration processes induce epithelial remodeling such as hyperplasia, metaplasia, and fibrosis. Understanding the sequence of processes involved in cell proliferation and differentiation is therefore of crucial importance. Both
in vivo and
in vitro, human airway basal cells are able to proliferate and reconstitute a fully differentiated and functional epithelium.
2 These cells are such considered as progenitors of the human airway epithelium and important actors of the airway epithelium regeneration.The nonneuronal cholinergic system is thought to be involved in the regulation of cell functions such as cell-cell interaction, apoptosis, and proliferation.
3 It is now established that human bronchial epithelial cells contain all of the machinery for the production, storage, secretion, and degradation of acetylcholine, which acts as an autocrine or paracrine hormone.
4,5 Acetylcholine exerts its effects through muscarinic and nicotinic acetylcholine receptors. Nicotinic acetylcholine receptors (nAChRs) are composed of five subunits, arranged as α/β heteromeric or α homomeric nAChRs, and assembled around a central ion channel, mediating the influx of Ca
2+.
6 The airway epithelium expresses α3, α4, α5, α7, α9, β2, and β4 subunits for nAChRs.
7,8,9α7 nAChR is characterized by an elevated Ca
2+ permeability
10 and has been involved in several important biological processes such as cell proliferation, apoptosis, and angiogenesis in cancer.
11,12 Prenatal nicotine exposure significantly increases pulmonary α7 nAChR expression and alters fetal lung development
13 and subsequently pulmonary function in newborn.
14 In particular, alteration of lung branching morphogenesis induced by nicotine is mediated by α7 nAChR.
15 Altogether, these observations led us to investigate whether the α7 nAChR could be involved in the differentiation of the respiratory epithelium. In the human airway epithelium, we observed α7 nAChR expression in basal cells, which play a critical role in the epithelial regeneration. Both
in vivo and
in vitro, the α7 nAChR expression is associated with the airway epithelium differentiation. Moreover,
in vitro inactivating α7 nAChR or
in vivo disrupting genetic α7 nAChR expression induces airway epithelium remodeling by modulating basal cell proliferation. This study thus provides several lines of evidence that α7 nAChR is significant for airway epithelial differentiation and suggests that α7 nAChR is a key regulator of the plasticity of the airway epithelium.
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