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WIREs Dev Biol
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Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease

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Abstract The lung has vital functions in gas exchange and immune defense. To fulfill these functions the cellular composition and complex three‐dimensional organization of the organ must be maintained for a lifetime. Cell turnover in the adult lung is normally low. However, in response to cellular injury by agents such as infection, toxic compounds, and irradiation there is rapid proliferation and differentiation of endogenous stem and progenitor cells to repair and regenerate the damaged tissue. In the mouse, different populations of epithelial progenitor cells have been identified in different regions of the respiratory system: basal cells in the proximal tracheobronchial region and submucosal glands, and secretory cells in the conducting airways and bronchioalveolar duct junction. The identification of the long‐term stem cells in the alveolar region is still under debate, and little is known about resident stem and progenitor cells for the many mesodermal populations. Within this framework information is provided about the origin of lung progenitor cells during development, the microenvironment in which they reside, the experimental injury and repair systems used to promote their regenerative response, and some of the mechanisms regulating their behavior. WIREs Dev Biol 2013, 2:131–148. doi: 10.1002/wdev.58 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease

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Schematic representation of the small bronchioles, bronchioalveolar duct junction and alveoli of adult mouse lung showing the diversity of epithelial and mesenchymal cell types. The intralobar airways of the mouse lung lack BCs except in the most proximal regions. At the BADJ there are a few ‘variant’ Clara cells that are resistant to naphthalene (light blue). These may or may not be the same as putative BASCs that express both Scgb1a1 and Sftpc protein (green/blue). Three subtypes of Type II cells have been described; those that express large amounts of surfactant protein C (Sftpc) in lamellar bodies (dark green), a minority that co‐express Scgb1a1 and Sftpc51 and those that express integrin α6β4 and no or low levels of Sftpc (dotted, light green). It has been proposed that the latter are long‐term stem cells of the Type II population.24 Lineage‐tracing data show that Type II cells can give rise to Type I cells (pink).29 The mesenchymal population that contributes to the microenvironment of the epithelial cells is diverse and relatively poorly characterized and little is known about lineage relationships. A blood vessel (Bv) is typically found in association with the BADJ but there is no dedicated blood supply to the bronchioles. Fibroblast‐like cells have been described in very close association with Type II cells (brown) and with projections to pericytes and vascular endothelium.31 In some cases fibroblasts adjacent to Type II have lipid inclusions and have been called lipofibroblast (brown/yellow).32 Pericytes (dark yellow) are present in association with larger Bvs and capillaries in the septae.27

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Submucosal glands contain basal cells (BCs) in the ducts and myoepithelial (ME) cells in the acini. Section of a submucosal gland in the mouse trachea (a) stained for Krt14 and Smooth Muscle Actin (Sma). Higher magnification (b) shows clear co‐expression of Krt14 and SMA in the ME cells of the acini, whereas duct BCs express Krt14 (and Trp63 and Krt5, not shown).

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Schematic representation of the tracheobronchial region of the mouse lung. Basal cells (BCs) that are Krt5+, Trp63+, and Ngfr+ (light orange) are dispersed throughout the tracheobronchial region in close association with the basal lamina (dotted line). In steady state, a few BCs in the surface epithelium, and most in the submucosal gland ducts, also express Krt14 (red). The immediate microenvironment of the BCs is made up of neighboring luminal epithelial cells—mostly multiciliated (light yellow) and secretory cells (blue and purple)—to which they are attached by desmosomes. The epithelium also contains myeloid cells, including dendritic cells (dark yellow). The intercartilage regions are enriched in nerves and Bvs of the dedicated bronchial circulation. The vessels undergo remodeling postnatally50 and the endothelial cells and associated vascular smooth muscle and pericytes (not shown) are in close association with the epithelium. In the dorsal trachea there is no cartilage, but more airway smooth muscle (dark orange) immediately underneath the basal lamina. The subepithelial mesenchyme includes ‘interstitial fibroblasts’ (gray).

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Schematic representation of some significant differences between human and mouse lungs. The internal diameter of the mouse trachea (∼1.5 mm) is about the same as that of a terminal airway in the human. The average alveolar volume in humans is 4.2 × 106 µm3, whereas it is only 2.2 × 104 µm3 in C57/BL/6J mice.43,44 In the mouse, cartilage rings (white) are restricted to the trachea and main stem bronchi, while in humans cartilage plates are found deep within the lung. Submucosal glands (SMGs) are restricted to the most proximal region of the trachea in the mouse, but are present much further into the lung in humans. More goblet cells (dark blue) are present in humans than mouse and Clara cells (light blue) are mostly confined to the smallest airways (∼1 mm diameter).45 Significantly, a pseudostratified epithelium with basal cells lining the intralobar airways of the human lung, right down to the terminal bronchioles.20,46 These are the sites of major obstruction and pathology in disorders such as chronic obstructive airway disease and asthma.7,8,20,47 Little is known about the phenotype of the epithelium of the smallest respiratory bronchioles of the human lung.48,49

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Model of injury/repair and the niche of BCs. According to this simplified model luminal cells exposed to toxic compounds, oxidative agents, or infection become stressed and/or die and slough off. Stressed cells release cytokines (purple) such as IL‐6, IL‐1β, TNF‐α, and chemokines that attract immune cells and may also act directly on surviving basal stem cells (green). These spread and attempt to restore barrier function. In response to multiple inputs from the niche (stroma, Bvs, nerves, stressed luminal cells, immune cells, etc.) they proliferate and generate undifferentiated early progenitors (pink)66 that give rise to differentiated secretory and ciliated cells. A functional epithelium may be restored within 2 weeks.

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