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Logo of patsIssue Featuring ArticlePublisher's Version of ArticleSubmissionsAmerican Thoracic SocietyAmerican Thoracic SocietyProceedings of the American Thoracic Society
Proc Am Thorac Soc. 2008 April 15; 5(3): 328–333.
PMCID: PMC2645243

Maintenance and Repair of the Bronchiolar Epithelium


Bronchioles of the distal conducting airway are lined by a simple epithelium composed primarily of nonciliated secretory (Clara) cells and ciliated cells. These cells are long-lived in the normal lung; renewal is mediated by cells that constitute a nonclassical stem cell hierarchy. Within this type of hierarchy, facultative progenitor cells are responsible for normal epithelial maintenance and rare adult tissue-specific stem cells are activated only in response to depletion of the facultative progenitor cell pool. This organizational structure is a departure from the classical stem cell hierarchies that maintain rapidly renewing tissues such as the epithelium of the small intestine. This article compares cellular and molecular mechanisms of epithelial renewal in the relatively quiescent bronchiolar epithelium and in the mitotically active intestinal epithelium. Fundamental distinctions between stem cell hierarchies of slowly and rapidly renewing epithelia are highlighted and may provide insight into tissue-specific interpretation of signals that mediate repair in some tissues but lead to remodeling and chronic disease in other organ systems.

Keywords: stem cell, progenitor, bronchiole, repair

Mechanisms regulating tissue maintenance in the steady state and repair after injury vary considerably between organs. In this context, the rate of cell replacement in the normal condition is a distinctive functional property that allows classification of epithelia into two broad subsets: rapidly renewing and slowly renewing. Clear distinctions in both the cellular organization and molecular regulation of tissue replacement can be made between these classes of tissues. The epithelium lining the gut turns over rapidly. Within the small intestine, specialized cell types lining villi are postmitotic and these differentiated cell types are replaced every 3 to 5 days (1). Constant renewal of villus epithelial cells requires frequent stem cell proliferation for the generation of large numbers of transit-amplifying cells (2). The transit-amplifying cell, like the tissue stem cell, proliferates frequently but eventually commits to the differentiation pathway. Rapid cellular renewal serves to maintain epithelial function and barrier properties in the harsh environment of the intestinal lumen. The epidermis and esophagus are other examples of rapidly renewing tissues whose rate of turnover serves to maintain an intact barrier against the external environment (3). However, the rate of differentiated cell turnover is considerably slower in many other tissues, yet can increase dramatically after injury. These include internal organs such as the pancreas, liver, and thymus, which have no direct exposure to the external environment, as well as the lung, which has elaborate defense mechanisms to avoid injury by inhaled environmental agents.

Here we discuss mechanisms of epithelial maintenance within the slowly renewing bronchiole and relate this to what is known in the rapidly renewing epithelium of the small intestine. We suggest that the multifunctional role of Clara cells in lung homeostasis defines this cell population as a facultative progenitor cell. Clara cells perform specialized functions necessary for host defense in the normal state but retain the ability to proliferate in response to injury. Facultative progenitor cells are also found in other slowly renewing tissues, such as the liver (hepatocyte), pancreas (β cell), and thymus (cortical and medullary epithelial cells). These cells may represent a previously unrecognized tier of stem cell hierarchies specific to slowly regenerating epithelia. The broad distribution of the facultative progenitor cells within these tissues suggests that the organization of such nonclassical stem cell hierarchies is distinct from that of rapidly renewing tissues and that novel signaling mechanisms regulate proliferation, differentiation, and migration within these tissues. This discussion was presented at the Aspen Lung Conference on Lung Injury and Repair in June 2007.


Epithelial maintenance as well as renewal after injury to ciliated cells is associated with proliferation of endogenous nonciliated epithelial cells. The steady-state proliferative index of the airway epithelium is low, with approximately 1% of bronchiolar epithelial cells entering the S-phase of the cell cycle within a 24-hour period (4). This rate increases by greater than 10-fold after injury. Cells that incorporate [3H]-thymidine in the steady-state epithelium or after NO2-induced depletion of ciliated cells were shown to be a subpopulation of bronchiolar nonciliated cells that lacked the typical features of differentiated cells, such as secretory granules and smooth endoplasmic reticulum (5). This cell type, termed the “type A cell,” was shown by pulse-chase methods to be a derivative of the Clara cell (6). These studies demonstrated that Clara cells of the normal adult bronchiolar epithelium exhibit differentiated character, yet retained the capacity to proliferate in response to normal cell attrition or injury.

We suggest that the abundant Clara cells of mammalian bronchiolar airways constitute a large pool of broadly distributed facultative progenitor cells that are capable of effecting repair of a normally quiescent epithelium. After restoration of normal physiologic conditions, the mitotic type A cell returns to the quiescent Clara cell state. As such, the reparative capacity of bronchiolar airways is conditional rather than obligate. Thus, in stark contrast with the intestine, which is reliant on a rare stem cell and spatially restricted stem/transit-amplifying cell compartment, maintenance and renewal of the bronchiolar epithelium is dependent on transient activation of a facultative progenitor to its proliferative form. Within this tissue, adult tissue stem cells are activated only in response to depletion of the facultative progenitor cell pool. Thus, reparative mechanisms are highly specialized in slowly and rapidly renewing epithelia and these adaptations are likely to be a reflection of anatomic, physiologic, and functional constraints of the organs in which they reside.


Utilization of an abundant, broadly distributed facultative progenitor cell for bronchiolar homeostasis and repair meets the functional constraints of this organ. The slow replacement kinetics observed for the conducting airway epithelium results from the effective integration of functions contributing to host defense with those contributing to maintenance of reparative capacity. In contrast, the harsh environment within the intestinal lumen requires rapid replacement of the intestinal epithelium for maintenance of function. The requirement for rapid cell replacement is met through continuous proliferation of tissue stem cells and their descendents, transit-amplifying cells. These highly mitotic cell types lack differentiated characteristics seen among epithleial cells lining the villus and are sequestered within protective microenvironments termed the “crypts of Leiberkuhn.” This anatomic organization results in protection of the proliferative compartment responsible for maintenance of the epithelium without compromising absorptive and protective functions of epithelium in direct contact with the intestinal lumen. Thus, architectural adaptations that suit the distinct functional characteristics of the bronchiole and intestine are tightly coupled with the unique characteristics of progenitor cell types within these organs.

Because bronchiolar facultative progenitor cells are abundant and broadly distributed, they are uniquely positioned to effectively coordinate critical aspects of the epithelial response to environmental exposures. In the steady state, these cells secrete low-molecular-weight proteins and chemical mediators important in host defense. Apically secreted proteins function in immunoregulation (79), in protection from environmental agents (10, 11), and potentially in coordination of mechanical activities such as mucociliary clearance (12). Facultative progenitor cells of the airway are also a source of mucus proteins important for bacterial clearance (13, 14). As the preferred progenitor cell within airways and in the alveolar epithelium (6, 15), the facultative progenitor cell population represents a vast repository of cells that can respond on a cell-by-cell basis to environmental exposures. Consequently, dual functionality of the bronchiolar facultative progenitor allows coordination of the response to acute stress or overt injury. Importantly, the response to environmental insult can be graded, allowing appropriate and site-specific regulation of magnitude and duration, and synchronization of the acute response with reparative mechanisms.

Properties of progenitor cells in slowly renewing organs vary between normal and injured conditions. In the steady state, facultative bronchiolar progenitor cells fulfill functions analogous to postmitotic secretory and absorptive cells of the villus epithelium in the steady state. Airway injury results in a transient change in the facultative progenitor, leading to loss of “differentiated” ultrastructural character and assumption of a less differentiated phenotype that is analogous to that of the obligate progenitor of the intestinal crypt. This “undifferentiated” state is maintained for a period of days after acute airway injury and is followed by differentiation of the nascent epithelium to reestablish mucociliary functions typical of the quiescent state (6). Thus, the abundance and broad distribution of the facultative progenitor endow the bronchiolar epithelium with a high degree of functional flexibility and the capacity to respond rapidly to depletion of long-lived cell types.

Unlike the slow replacement kinetics of the normal bronchiolar epithelium, turnover of the intestinal epithelium is a continuous and rapid process. This disparity in the normal replacement kinetics of the lung and intestinal epithelium is associated with fundamental differences in the distribution of available progenitor cells (16). The intestinal epithelium is partitioned into mitotic and differentiation compartments. The mitotic zone, the crypt of Lieberkuhn, is largely protected from the luminal contents. Within the small intestine, this epithelium is largely composed of undifferentiated cells that proliferate continuously and a less abundant population of differentiated Paneth cells residing at the base of the crypt. The progeny of mitotic crypt cells replace the transient population of postmitotic differentiated cells. The latter cell types are limited to fingerlike villi that project into the lumen of the small intestine or line a flat tubular lumen within the colon. Partitioning of the epithelium in such a manner provides the necessary differentiated cell types for absorptive and secretory functions that are critical at the villus–lumen interface, yet maintains a highly proliferative population of undifferentiated progenitor cells that are “protected” from the harsh environment of the intestinal lumen.

We suggest that the rate of epithelial renewal in the normal state dictates not only temporal partitioning of the functional states but also the need for spatial segregation of mitotic and differentiated epithelial cell types. The latter property is in turn related to the availability of sequestering microenvironments in obligate versus facultative states. Anatomic constraints of the airway preclude the existence of a distinct protective compartment necessary for protection of obligate progenitor cells, such as those of the intestinal crypt. Airways can accommodate the absence of a highly mitotic progenitor due to the slow rate of epithelial turnover and a sporadic requirement for activation of the facultative progenitor.


The definition of an adult tissue stem cell reflects the context in which it is viewed. The classical definition of an adult tissue stem cell is based on studies investigating the regenerative capacity of rapidly renewing tissues or cell types. Accordingly, a tissue-specific stem cell is one that self-renews and gives rise to each of the differentiated cell types within its native tissue. Availability of cell-type–specific markers and a robust functional assay allowed isolation of rare bone marrow–derived cells that fit this definition and hence definitive identification of a hematopoietic stem cell (17). However, cell selection and tissue reconstitution techniques are difficult to apply to solid tissues. As a consequence, in situ techniques were developed to segregate reparative cells on the basis of cell cycle frequency (1821) and differentiation potential (22, 23). Application of DNA pulse-chase labeling methods to rapidly renewing epithelia led to the designation of tissue-specific stem cells as a reparative cell that proliferates less frequently than its daughter cells, the transit-amplifying pool (otherwise referred to as the progenitor cell). As such, stem cells retain labeled DNA, whereas highly mitotic transit-amplifying cells dilute the marked DNA. A mechanistic explanation for the property of DNA label retention within the stem cell versus depletion within the transit-amplifying cell relates to the constant turnover of the differentiated cell pool. The need for constant replenishment of differentiated cell types, such as those of the villus epithelium, requires the continuous proliferation of the transit-amplifying pool. Because transit-amplifying cells have limited capacity for self-renewal, periodic stem cell activation is required to maintain the regenerative capacity of the epithelium. On the basis of this premise, stem and transit-amplifying cells should be functionally distinguished according to their proliferative frequency within a defined time period. However, recent studies investigating properties of the intestinal stem cell hierarchy argue that frequent proliferation may be a shared functional property of the stem and transit-amplifying cell populations (2). If validated, these studies suggest that alternative mechanisms are responsible for preservation of stem cell genomic integrity.

In contrast to the short half-life of differentiated cells within rapidly renewing epithelia, differentiated cells of the slowly renewing lung, liver, and pancreas epithelium are a relatively stable population (24). This distinction in the rate of epithelial turnover impacts the longevity of the facultative progenitor cell. Consequently, facultative progenitor cells that are specified during development may be maintained for a considerable fraction of the natural life of an organism and may constitute the dominant source of renewing cells in the adult tissue (25). Thus, longevity and cell cycle frequency do not readily distinguish stem, transit-amplifying, and facultative progenitor cells of these tissues in the normal state. Identification of stem cells in these tissues is highly dependent on effective depletion of the facultative progenitor. In these tissues, extensive injury results in limited proliferation of a spatially restricted cell and focal regeneration of the epithelium (2628). Thus, reparative cells of relatively quiescent epithelia must meet a broad set of phenotypic and functional criteria to be considered tissue stem cells. Importantly, such cells are defined as a rare cell type that is sequestered in a specialized microenvironment, lacks functional attributes that sensitize the facultative progenitor to environmental agents, and proliferates incrementally in response to injury. Within these nonclassical stem cell hierarchies, differentiation status rather than cell cycle frequency seems to be the critical distinction between the stem cell and other cells with mitotic potential. Moreover, the contribution made by stem cells to maintenance of the tissue is highly dependent on the lifespan of the facultative progenitor cell pool. Although tissue stem cells actively participate in the normal maintenance of rapidly renewing tissues, this is not the case for slowly renewing tissues (29). In slowly renewing organs, stem cell activation is part of an adaptive response to an increase in the rate at which differentiated cells and facultative progenitor cells are depleted.

Within the bronchiole, tissue-specific stem cells have been identified within the neuroepithelial body and bronchiolar duct junction microenvironments (30, 31). These cells are resistant to the Clara cell–specific toxicant naphthalene (4, 32). Pulse-chase studies in which the DNA of proliferating cells is labeled with either tritiated thymidine or bromodeoxyuridine indicate that this population gives rise to nascent secretory and ciliated cells and represents a long-term label-retaining population. Genetic ablation studies demonstrate that bronchiolar tissue–specific stem cells express the marker Clara cell secretory protein (CCSP) and that these cells are necessary for repair of the injured epithelium (30, 31, 33). In vitro analysis suggested the existence of a bronchoalveolar stem cell (34). However, lineage tracing analysis in vivo demonstrated a clear demarcation between the airway and alveolar compartments (S. D. Reynolds and colleagues, unpublished manuscript) and suggested segregation of these compartments from Embryonic Day 16.5 onward. The relationship between extensive depletion of the airway facultative progenitor cell and airway stem cell activation defines the Clara cell and the bronchiolar stem cell as a member of a nonclassical stem cell hierarchy.


The initial description of adult tissue stem cell hierarchies within rapidly renewing tissues led to use of these systems to define signaling pathways critical for regulation of proliferation, differentiation, and migration. Within these tissues, initial clues into regulatory mechanisms were provided through studies investigating molecular mechanisms of epithelial hyperplasia and tumorigenesis. Genetic perturbations involving components of the β-catenin destruction complex lead to uncontrolled proliferation of intestinal stem/transit cells, loss of their capacity for appropriate lineage specification and differentiation, and migratory defects (37). Direct roles for Wnt/β-catenin in mediating these outcomes have been implied from studies involving genetically modified mouse models, for which potentiation or inhibition of β-catenin signaling leads to either expansion or regression of the proliferative compartment within intestinal crypts, respectively, and loss of differentiated intestinal epithelial cells (37, 38). Potentiation of the Wnt/β-catenin pathway has similarly profound influences on the self-renewal capacity and differentiation potential of other stem cell hierarchies, such as those of the hematopoietic system (3942) or the epidermis (4346), leading in each case to expansion of the stem/progenitor cell pool and either arrested or altered differentiation. However, even though the Wnt/β-catenin pathway plays a critical role in regulation of lung development (4749), it is unclear if it fulfills similar roles in the maintenance of adult lung stem cells. We have used mouse models allowing conditional manipulation of β-catenin to reveal roles for this pathway in regulation of the bronchiolar stem cell hierarchy. We have established that potentiation of β-catenin signaling leads to the arrested differentiation of immature bronchiolar epithelial cells and stabilization in a state that closely resembles the bronchiolar stem cell (S. D. Reynolds, unpublished manuscript). However, we have also demonstrated that β-catenin signaling is not necessary for maintenance of the adult bronchiolar stem cell or regulation of other cellular components of the bronchiolar stem cell hierarchy (manuscript in preparation).

Further distinctions between classical and nonclassical stem cell hierarchies may derive from extrinsic factors that regulate the key events of tissue maintenance: proliferation, differentiation, and migration. Within the close confines of the intestinal crypt or the bulge region of the hair follicle, these processes may be coordinately regulated through extrinsic regulatory cues. By analogy with germline stem cells (35), the ability of a classical niche to harbor tissue stem cells may be conferred through integrin-mediated contacts with the extracellular matrix (17). Migration of cells away from the niche would attenuate this signaling process and render cells susceptible to alternative regulatory influences. Numerous paracrine factors impinge on mitotic cells of the crypt, including the multifunctional Wnt/β-catenin signaling pathway (36). Although this pathway is believed to act as a critical regulator of proliferation and differentiation, downstream effectors of migration may in fact function in establishment of the domain structure of the crypt–villus axis. Similar processes may be in play within nonclassical hierarchies and could account for spatial segregation of the stem cell and the facultative progenitor. However, the unique capacity for incremental proliferation by the broadly distributed facultative progenitor cell pool predicts utilization of signaling pathways distinct from those critical to organization of rapidly renewing tissues.

Even though our studies question the importance of the Wnt/β-catenin signaling pathway in regulation of the adult bronchiolar stem cell hierarchy, they suggest an important role for β-catenin signaling in modulating differentiation of bronchiolar epithelial cells and establishment of the stem cell hierarchy during late lung development. The apparent paradox in which active β-catenin signaling is sufficient to preserve the stem cell phenotype but is unnecessary for adult stem cell maintenance suggests that other signaling pathways regulate stem cell activity within the adult niche. Studies in epidermis suggest that distinct signals may regulate steady-state proliferation of the stem cell compartment and stem cell maintenance (50, 51). However, it is likely that many signaling pathways interact to mediate normal regulation of the proliferative and differentiation responses of a tissue stem cell hierarchy, and roles for these signals in regulation of the reparative characteristics of different organs are likely to be highly tissue specific.


Facultative progenitor cells exhibit profound phenotypic plasticity that facilitates protection of the epithelium but may also hinder its progenitor function (13, 14). Terminal airways of patients with asthma and patients with chronic obstructive pulmonary disease undergo metaplastic transition to a mucosecretory phenotype, a cellular response that does not alter cell density (52). Thus, chronic mucosecretory disease may represent a situation in which epithelial regeneration is compromised but not severe enough to activate latent tissue-specific stem cells. In contrast, depletion of normal and mucosecretory cell types has been reported in severe lung disease, particularly end-stage asthma and bronchiolitus obliterans–associated lung transplantation (5355). These circumstances mimic those associated with tissue-specific stem cell activation in animal models but do not lead to epithelial regeneration. Clearly, additional studies in mice are needed to determine the impact of ongoing disease on stem cell activation. In particular, functionality of the stem cell population in the context of inflammatory mediators central to progression of these chronic lung diseases is of critical import.

Transition of lung progenitor cells from a facultative to an obligate progenitor state may contribute to initiation or perpetuation of chronic lung disease. As indicated above, participation of the Clara cell population in epithelial regeneration is an acute response to cell attrition or injury. Entry of the Clara cell into the cell cycle is accompanied by loss of differentiated functions, such as secretion of the major Clara cell product, CCSP. Extensive analysis of CCSP protein levels in acute and chronic lung disease suggests that differentiated functions of the facultative progenitor are compromised (56), potentially as a consequence of continuous proliferation. If confirmed, conversion of the facultative progenitor to an obligate progenitor may also exhaust the proliferative potential of this cell type. Senescence of the Clara cell would leave the epithelium deficient in both differentiated and regenerative functions. Thus, transition from a facultative to an obligate progenitor may result in a cascade of changes that contribute to epithelial fragility through loss of cellular autocrine/paracrine-protective mechanisms, epithelial hypoplasia, and dysregulation of interactions between the epithelial, mesenchymal, and vascular compartments.

Tumor initiation within various epithelia has been attributed to mitotic activation of a postmitotic cell type or transformation of a tissue stem cell (57). Either mechanism may result in establishment of a cancer stem cell that is relatively quiescent and resistant to chemotherapeutic drugs that target actively cycling cells. Within the lung, facultative progenitor cells of the airway and alveolar epithelium have been implicated as precursors to non–small cell lung carcinoma. Because these cells have a native capacity to proliferate, mechanisms regulating their initial transition to a tumorigenic phenotype are likely to be distinct from those regulating formation of precancerous lesions by postmitotic cells of the intestine. Importantly, tumor initiation may be the rate-limiting step in transformation of differentiated intestinal cells, whereas tumor progression may be a key regulator in lung cancer. Bronchiolar stem cells may also function as tumor-initiating cells (34, 58), and mechanisms regulating their contribution to lung cancer may be more similar to those governing tumors derived from facultative progenitor cells than those from obligate stem cells of the gut. Thus, comparative analysis of molecular mechanisms regulating stem cell activity in classical and nonclassical stem cell hierarchies may lend itself to a better understanding of organ-specific aspects of oncogenesis and development of treatment strategies that take into account these differences.


The long-standing interests of many laboratories in understanding the process of airway injury and repair have provided important insights into both cellular and molecular mechanisms. These studies define components of the airway stem cell hierarchy and how cell types of this hierarchy participate in steady-state maintenance of the epithelium in addition to repair after injury. Critical gaps in our knowledge relate to the precise molecular regulation of the reparative process and long-term maintenance of reparative capacity. Further insights into these processes will require development of improved methods for identification and manipulation of distinct cell types within the lung. Ultimately, the capacity to recapitulate aspects of the biology in vitro and subsequently validate findings by reconstituting and/or precisely manipulating the in vivo system will be key to future progress. These studies will provide the foundation on which translational studies aimed at modulating tissue reparative capacity may be performed, with the goal of developing novel interventions for debilitating lung diseases in humans.


  • Progenitor cell: A collective term used to describe any cell that has the capacity to proliferate. The term progenitor cell is commonly used to indicate a cell that is in the process of cell division or has the potential to enter the cell cycle. Terminology that takes into account the functional distinctions among progenitor cells is suggested below.
  • Adult tissue stem cell: A relatively undifferentiated cell that has the capacity for unlimited self-renewal through stable maintenance within a stem cell niche. Adult tissue stem cells have a differentiation potential equivalent to the cellular diversity of the tissue in which they reside. The hematopoietic stem cell is a prototypical adult tissue stem cell.
  • Transit-amplifying cell: The progeny of a tissue stem cell that retain relatively undifferentiated character and have a finite capacity for proliferation. The sole function of transit-amplifying cells is generation of sufficient specialized progeny for tissue maintenance.
  • Obligate progenitor: A cell that loses its ability to proliferate once it commits to a differentiation pathway. Intestinal transit-amplifying cells are obligate progenitor cells.
  • Facultative progenitor: A cell that exhibits differentiated features when in the quiescent state yet has the capacity to proliferate for normal tissue maintenance and in response to injury. Bronchiolar Clara cells are an example of this cell type.
  • Classical stem cell hierarchy: A stem cell hierarchy in which the adult tissue stem cell actively participates in normal tissue maintenance and gives rise to a transit-amplifying cell. Within this type of hierarchy, renewal potential resides in cells at the top of the hierarchy (i.e., the stem and transit-amplifying cell).
  • Nonclassical stem cell hierarchy: A stem cell hierarchy in which the adult tissue stem cell does not typically participate in normal tissue maintenance but can be activated to participate in repair after progenitor cell depletion.
  • Rapidly renewing tissue: Tissues in which homeostasis is dependent on maintenance of an active mitotic compartment. Specialized cell types are located in a spatially distinct compartment and have a short half-life. Rapid turnover of differentiated cell types requires continuous proliferation of stem and/or transit-amplifying cells. The prototypical rapidly renewing tissue is the intestinal epithelium.
  • Slowly renewing tissue: Tissues in which the steady-state mitotic index is very low. Specialized cell types are broadly distributed and long-lived, and a subset of these cells, the facultative progenitor cell, retains the ability to enter the cell cycle. The relative stability of the differentiated cell pool is paralleled by infrequent proliferation of stem and/or transit-amplifying cells. The lung is an example of a slowly renewing tissue.


Supported by the National Heart, Lung, and Blood Institute (HL064888 [B.R.S.], HL090146 [B.R.S.], HL075585 [S.D.R.]).

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.


1. Marshman E, Booth C, Potten CS. The intestinal epithelial stem cell. Bioessays 2002;24:91–98. [PubMed]
2. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007;449:1003–1007. [PubMed]
3. Fuchs E. Scratching the surface of skin development. Nature 2007;445:834–842. [PMC free article] [PubMed]
4. Reynolds SD, Giangreco A, Power JH, Stripp BR. Neuroepithelial bodies of pulmonary airways serve as a reservoir of progenitor cells capable of epithelial regeneration. Am J Pathol 2000;156:269–278. [PubMed]
5. Evans MJ, Johnson LV, Stephens RJ, Freeman G. Renewal of the terminal bronchiolar epithelium in the rat following exposure to NO2 or O3. Lab Invest 1976;35:246–257. [PubMed]
6. Evans MJ, Cabral-Anderson LJ, Freeman G. Role of the Clara cell in renewal of the bronchiolar epithelium. Lab Invest 1978;38:648–653. [PubMed]
7. Watson TM, Reynolds SD, Mango GW, Boe IM, Lund J, Stripp BR. Altered lung gene expression in CCSP-null mice suggests immunoregulatory roles for Clara cells. Am J Physiol Lung Cell Mol Physiol 2001;281:L1523–L1530. [PubMed]
8. Wang SZ, Rosenberger CL, Espindola TM, Barrett EG, Tesfaigzi Y, Bice DE, Harrod KS. CCSP modulates airway dysfunction and host responses in an Ova-challenged mouse model. Am J Physiol Lung Cell Mol Physiol 2001;281:L1303–L1311. [PubMed]
9. Harrod KS, Mounday AD, Stripp BR, Whitsett JA. Clara cell secretory protein decreases lung inflammation after acute virus infection. Am J Physiol 1998;275:L924–L930. [PubMed]
10. Plopper CG, Mango GW, Hatch GE, Wong VJ, Toskala E, Reynolds SD, Tarkington BK, Stripp BR. Elevation of susceptibility to ozone-induced acute tracheobronchial injury in transgenic mice deficient in Clara cell secretory protein. Toxicol Appl Pharmacol 2006;213:74–85. [PubMed]
11. Mango GW, Johnston CJ, Reynolds SD, Finkelstein JN, Plopper CG, Stripp BR. Clara cell secretory protein deficiency increases oxidant stress response in conducting airways. Am J Physiol 1998;275:L348–L356. [PubMed]
12. Reynolds SD, Reynolds PR, Snyder JC, Whyte F, Paavola KJ, Stripp BR. CCSP regulates cross talk between secretory cells and both ciliated cells and macrophages of the conducting airway. Am J Physiol Lung Cell Mol Physiol 2007;293:L114–L123. [PubMed]
13. Evans CM, Williams OW, Tuvim MJ, Nigam R, Mixides GP, Blackburn MR, DeMayo FJ, Burns AR, Smith C, Reynolds SD, et al. Mucin is produced by Clara cells in the proximal airways of antigen-challenged mice. Am J Respir Cell Mol Biol 2004;31:382–394. [PubMed]
14. Reader JR, Tepper JS, Schelegle ES, Aldrich MC, Putney LF, Pfeiffer JW, Hyde DM. Pathogenesis of mucous cell metaplasia in a murine asthma model. Am J Pathol 2003;162:2069–2078. [PubMed]
15. Evans MJ, Dekker NP, Cabral-Anderson LJ, Freeman G. Quantitation of damage to the alveolar epithelium by means of type 2 cell proliferation. Am Rev Respir Dis 1978;118:787–790. [PubMed]
16. Pinto D, Clevers H. Wnt control of stem cells and differentiation in the intestinal epithelium. Exp Cell Res 2005;306:357–363. [PubMed]
17. Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell 2004;116:769–778. [PubMed]
18. Morris RJ, Fischer SM, Slaga TJ. Evidence that a slowly cycling subpopulation of adult murine epidermal cells retains carcinogen. Cancer Res 1986;46:3061–3066. [PubMed]
19. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61:1329–1337. [PubMed]
20. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 1989;57:201–209. [PubMed]
21. Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E. Defining the epithelial stem cell niche in skin. Science 2004;303:359–363. [PMC free article] [PubMed]
22. Wong MH, Saam JR, Stappenbeck TS, Rexer CH, Gordon JI. Genetic mosaic analysis based on Cre recombinase and navigated laser capture microdissection. Proc Natl Acad Sci USA 2000;97:12601–12606. [PubMed]
23. Shapiro SD, Ingenito EP. The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years. Am J Respir Cell Mol Biol 2005;32:367–372. [PubMed]
24. Dor Y, Melton DA. How important are adult stem cells for tissue maintenance? Cell Cycle 2004;3:1104–1106. [PubMed]
25. Stanger BZ, Tanaka AJ, Melton DA. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 2007;445:886–891. [PubMed]
26. Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 2001;33:738–750. [PubMed]
27. Kawasaki E, Abiru N, Eguchi K. Prevention of type 1 diabetes: from the view point of beta cell damage. Diabetes Res Clin Pract 2004;66:S27–S32. [PubMed]
28. Mahvi D, Bank H, Harley R. Morphology of a naphthalene-induced bronchiolar lesion. Am J Pathol 1977;86:558–572. [PubMed]
29. Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004;429:41–46. [PubMed]
30. Giangreco A, Reynolds SD, Stripp BR. Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am J Pathol 2002;161:173–182. [PubMed]
31. Hong KU, Reynolds SD, Giangreco A, Hurley CM, Stripp BR. Clara cell secretory protein–expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am J Respir Cell Mol Biol 2001;24:671–681. [PubMed]
32. Stripp BR, Maxson K, Mera R, Singh G. Plasticity of airway cell proliferation and gene expression after acute naphthalene injury. Am J Physiol 1995;269:L791–L799. [PubMed]
33. Reynolds SD, Hong KU, Giangreco A, Mango GW, Guron C, Morimoto Y, Stripp BR. Conditional clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am J Physiol Lung Cell Mol Physiol 2000;278:L1256–L1263. [PubMed]
34. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121:823–835. [PubMed]
35. Tanentzapf G, Devenport D, Godt D, Brown NH. Integrin-dependent anchoring of a stem-cell niche. Nat Cell Biol 2007;9:1413–1418. [PMC free article] [PubMed]
36. He XC, Yin T, Grindley JC, Tian Q, Sato T, Tao WA, Dirisina R, Porter-Westpfahl KS, Hembree M, Johnson T, et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet 2007;39:189–198. [PubMed]
37. Radtke F, Clevers H, Riccio O. From gut homeostasis to cancer. Curr Mol Med 2006;6:275–289. [PubMed]
38. Sansom OJ, Reed KR, Hayes AJ, Ireland H, Brinkmann H, Newton IP, Batlle E, Simon-Assmann P, Clevers H, Nathke IS, et al. Loss of APC in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 2004;18:1385–1390. [PubMed]
39. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 2006. [PubMed]
40. Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, Leutz A. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol 2006. [PubMed]
41. Trowbridge JJ, Xenocostas A, Moon RT, Bhatia M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med 2006;12:89–98. [PubMed]
42. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423:409–414. [PubMed]
43. Gat U, DasGupta R, Degenstein L, Fuchs E. De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 1998;95:605–614. [PubMed]
44. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. Beta-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 2001;105:533–545. [PubMed]
45. Millar SE, Willert K, Salinas PC, Roelink H, Nusse R, Sussman DJ, Barsh GS. WNT signaling in the control of hair growth and structure. Dev Biol 1999;207:133–149. [PubMed]
46. Lo Celso C, Prowse DM, Watt FM. Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 2004;131:1787–1799. [PubMed]
47. Okubo T, Hogan BL. Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm. J Biol 2004;3:11. [PMC free article] [PubMed]
48. Mucenski ML, Wert SE, Nation JM, Loudy DE, Huelsken J, Birchmeier W, Morrisey EE, Whitsett JA. Beta-catenin is required for specification of proximal/distal cell fate during lung morphogenesis. J Biol Chem 2003;278:40231–40238. [PubMed]
49. Shu W, Guttentag S, Wang Z, Andl T, Ballard P, Lu MM, Piccolo S, Birchmeier W, Whitsett JA, Millar SE, et al. Wnt/beta-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Dev Biol 2005;283:226–239. [PubMed]
50. Kobielak K, Stokes N, de la Cruz J, Polak L, Fuchs E. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc Natl Acad Sci USA 2007;104:10063–10068. [PubMed]
51. Kobielak K, Pasolli HA, Alonso L, Polak L, Fuchs E. Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA. J Cell Biol 2003;163:609–623. [PMC free article] [PubMed]
52. Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 2001;164:S28–S38. [PubMed]
53. Shijubo N, Itoh Y, Yamaguchi T, Imada A, Hirasawa M, Yamada T, Kawai T, Abe S. Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med 1999;160:930–933. [PubMed]
54. Mattsson J, Remberger M, Andersson O, Sundberg B, Nord M. Decreased serum levels of Clara cell secretory protein (CC16) are associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell transplantation. Transplantation 2005;79:1411–1416. [PubMed]
55. Zhang Y, Wroblewski M, Hertz MI, Wendt CH, Cervenka TM, Nelsestuen GL. Analysis of chronic lung transplant rejection by MALDI-TOF profiles of bronchoalveolar lavage fluid. Proteomics 2006;6:1001–1010. [PubMed]
56. Broeckaert F, Clippe A, Knoops B, Hermans C, Bernard A. Clara cell secretory protein (CC16): features as a peripheral lung biomarker. Ann N Y Acad Sci 2000;923:68–77. [PubMed]
57. Hill RP, Perris R. Destemming cancer stem cells. J Natl Cancer Inst 2007;99:1435–1440. [PubMed]
58. Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, Jacks T, Tuveson DA. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 2001;15:3243–3248. [PubMed]

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