The glandular stem/progenitor cell niche in airway development and repair

Abstract

Airway submucosal glands (SMGs) are major secretory structures that lie beneath the epithelium of the cartilaginous airway. These glands are believed to play important roles in normal lung function and airway innate immunity by secreting antibacterial factors, mucus, and fluid into the airway lumen. Recent studies have suggested that SMGs may additionally serve as a protective niche for adult epithelial stem/progenitor cells of the proximal airways. As in the case of other adult stem cell niches, SMGs are believed to provide the localized environmental signals required to both maintain and mobilize stem/progenitor cells, in the setting of normal cellular turnover or injury. Aberrant proliferation and differentiation of glandular stem/progenitor cells may be associated with several hypersecretory lung diseases, including chronic bronchitis, asthma, and cystic fibrosis. To better understand the molecular mechanisms that regulate the specification and proliferation of glandular stem/progenitor cells in lung diseases associated with SMG hypertrophy and hyperplasia, researchers have begun to search for the molecular signals and cell types responsible for establishing the glandular stem/progenitor cell niche, and to dissect how these determinants of the niche change in the setting of proximal airway injury and repair. Such studies have revealed certain similarities between stem/progenitor cell niches of the distal conducting airways and the SMGs of the proximal airways.

Figure 1.

Label-retaining cells localize to submucosal glands in mouse trachea. Naphthalene-induced injury to mouse tracheal epithelia was followed by systemic bromodeoxyuridine (BrdU) labeling for 3 days. BrdU-labeled cells (termed labeling-retained cells [LRCs]) were localized in tracheal tissue sections using fluorescein isothiocyanate–labeled anti-BrdU antibodies. (A) Submucosal glands (SMGs), with relatively frequent cell labeling with BrdU at 21 days post–napthalene injury and pulse labeling with BrdU. These labeled cells likely include both labeled transient amplifying progenitor cells and stem cells. (B) By 90 days post–napthalene injury and BrdU labeling, BrdU-positive cells are seen less frequently in SMGs. These LRCs are considered as candidate stem cells of the glands. Nuclei are counterstained with DAPI. SAE = surface airway epithelium. Original magnification of microscope objective is given for each panel.

Figure 2.

Illustration of putative stem cell niches in the adult mouse lung. Epithelia of the adult mouse lung can be divided into four major, biologically distinct trophic units (trachea, bronchi, bronchioles, and alveoli), each of which encompasses unique types of airway epithelial cells (epithelia relevant to each unit are shown inside circles). Five potential stem cell niches for these various trophic units are shown on the right, with locations of candidate stem cells marked by arrowheads (cells are in red). Stem cells and niches include the following: (1) an unknown cell type in the submucosal gland (SMG) ducts of the proximal trachea, (2) basal cells in the intercartilaginous zones of the lower trachea and bronchi (these structures may also be associated with innervated neuroendocrine bodies [NEBs]), (3) variant Clara cells (Clara^v) associated with NEBs in bronchioles, (4) Clara^v cells associated with bronchiolar alveolar duct junctions (BADJ), and (5) alveolar type II cells of the alveoli.