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First published online 30 May 2006
doi: 10.1242/dev.02407

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Epithelial stem cells of the lung: privileged few or opportunities for many?

¹ Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
² Program in Stem Cell Research, Duke University Medical Center, Durham, NC 27710, USA.
³ Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.

View larger version (49K): [in a new window]   Fig. 1. Classical stem cell hierarchy. Model of the `classical' hierarchy of undifferentiated epithelial stem cell, transit amplifying (TA) progenitor cells and mature postmitotic differentiated cells. Cell fate choices are indicated by red arrows. In this model, the stem cell in its `niche' and different TA cell subclasses can self-renew (curved arrows). Stem cells self-renew infrequently and TA cells more rapidly. Early TA cells may be able to replace stem cells if the niche is depleted (dashed arrow 1). The niche probably consists of several cell types and associated molecules, including blood vessels and nerves. `Transdifferentiation' of one well-defined differentiated cell type into another could occur directly, without cell division (dashed arrow 2) or might also involve reversion or de-differentiation between distinct TA progenitor populations (dashed arrows 3). Rarely, stem cells switch from one tissue-specific lineage to another (dashed arrow 4) in a process called metaplasia or transdetermination (see Box 1). Adapted, with permission, from Watt and Hogan (Watt and Hogan, 2000).

View larger version (57K): [in a new window]   Fig. 2. A schematic of the main cell types along the proximodistal (rostrocaudal) axis of the mouse lung. Not all of the cartilage elements associated with the trachea and main bronchi are shown. Submucosal glands are present only in the upper part of the trachea in the mouse. The pseudostratified epithelium of the proximal airways contains mostly ciliated cells, which express the forkhead transcription factor Foxj1, Clara-like secretory cells [detected with antibody to Scgb1a1 (red)] and basal cells, detected with antibody to the transcription factor p63 (black). The bronchi also contain ciliated and Clara cells. They have many more neuroendocrine cells than the trachea, often in clusters at airway branch points, known as neuroendocrine bodies (NEBs), shown here by staining with antibody to calcitonin-gene related peptide (Cgrp, red). Each narrow bronchiolus opens into alveoli through a bronchioalveolar duct. This junction region is usually associated with a blood vessel (bv). The alveoli contain type II cells, which secrete large amounts of surfactant proteins [detected with antibody to surfactant protein C (Sftpc)]. The thin, flattened type I cells line the alveoli and are closely apposed by capillaries. Photographic images were all provided by E.R. from her own research material. The FoxJ1GFP transgenic mice used in one image were provided by Larry Ostwroski, University of North Carolina at Chapel Hill (NC, USA).

View larger version (35K): [in a new window]   Fig. 3. A schematic of the rat tracheal xenograft model. Image of nude mouse courtesy Charles River Laboratories.

View larger version (51K): [in a new window]   Fig. 4. Potential mechanisms involved in epithelial repair in the trachea and main bronchi. Clara-like cells are shown in blue, ciliated cells in green, neuroendocrine cells in pink, basal cells in orange and mucous cells in purple. Regions rich in blood vessels and nerves are indicated. Black line represents the basal lamina. Smooth muscle cells and fibroblasts are not shown. Putative regenerative cell populations are numbered 1-4. (1) K14-positive cells: these are possibly basal cells that self-renew and give rise to Clara cells and ciliated cells after destruction of Clara cells by naphthalene. (2) Label-retaining cells, which have been identified in submucosal gland ducts and in intercartilage regions. (3) Epithelial cells in submucosal glands, which can regenerate the entire luminal epithelium in grafts. (4) Clara cells, which can replace ciliated cells damaged by oxidants.

View larger version (20K): [in a new window]   Fig. 5. Potential repair mechanisms in the distal bronchi, bronchioles and alveoli. Type II alveolar cells are in yellow, type I alveolar cells are in gray, smooth muscle cells are in red. The broken red line indicates that blood vessels are associated with the bronchiolar epithelium but not obviously enriched in particular regions. In the alveoli, blood vessels are tightly apposed to type I cells. Putative regenerative cell populations are as follows (1-6). (1) Variant Clara (ClaraV) cells adjacent to neuroendocrine bodies (NEBs) and at bronchioalveolar junction (blue/pink or blue/yellow), which are resistant to naphthalene and proliferate soon after injury by this agent. If all Clara cells are destroyed, there is no repair and the mice die. (2) Putative bronchioalveolar stem cells (BASCs) (blue/yellow), which self-renew in culture after flow sorting and give rise to multiple lineages in culture. These may be the same as ClaraV cells. (3) Ciliated cells, which can proliferate and transdifferentiate into Clara cells after naphthalene injury but other evidence argues against this. (4) Clara cells, which proliferate after NO2 injury and give rise to ciliated cells but it is not known whether all Clara cells have this potential. (5) Type II cells, which give rise to type I cells after bleomycin injury to type I cells. (6) Neuroendocrine cells, where present, can self-renew and proliferate but do not give rise to other lineages.

View larger version (138K): [in a new window]   Fig. 6. Histological changes in the distal airway exposed to naphthalene. Changes in the mouse lung after exposure to naphthalene. (A) Section of a distal adult airway from a naphthalene-exposed mouse, showing abundant Clara cells (detected with antibody to Scgb1a1) and clusters of neuroendocrine (NE) cells (asterisk, stained with antibody to Cgrp). (B) A similar airway 24 hours after naphthalene exposure. Most Clara cells are lost, except for resistant cells close to NE cells and at the bronchioalveolar junctions (marked in both panels by white arrows). Images kindly provided by Adam Giangreco, Susan Reynolds and Barry Stripp (University of Pittsburgh, PA, USA).

View larger version (31K): [in a new window]   Fig. 7. A model showing putative stem cells in the distal lung. Left: depiction of the epithelial cell layer, with cells resting on a basal lamina (black line) and facing the lumen to the right. Stem cells are located in specific regions (red stars): ClaraV cells near neuroendocrine bodies (NEBs) and putative bronchioalveolar stem cells (BASCs) at the bronchioalveolar duct junction. Key indicates the different cell types possibly involved in steady-state turnover and injury response. The ClaraV and putative BASCs (which may be the same cells or members of the same stem cell population) differ from classical stem cells in that they co-express proteins also expressed by fully differentiated cell types. The existence of putative transit amplifying (TA) cells (hexagons), intermediate between stem cells and fully differentiated cells (squares) is hypothetical. Alternatively, Clara cells may be the TA population. A gradation of potential for self-renewal and contribution to different lineages might exist throughout the epithelium, with ClaraV and BASCs having the highest potential and fully differentiated cells the lowest.

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