Chapter Eight - Lung Stem and Progenitor Cells in Tissue Homeostasis and Disease
Introduction
The mammalian respiratory system is a highly complex three-dimensional organ historically described as containing over 40 different cell types, each with specialized functions to maintain adequate gas exchange and protect against environmental exposures. During development, the primordial lung undergoes branching morphogenesis to form the proximal conducting airways and distal gas-exchanging alveolar space (Morrisey & Hogan, 2010). The adult murine lung contains several distinct epithelial cell populations with unique anatomical positions and specialized functions (Fig. 8.1). The proximal airway includes the cartilaginous trachea, lined by pseudostratified columnar epithelial cells with submucosal glands interspersed. Noncartilaginous bronchioles, lined with simple columnar epithelium, branch from the trachea in an organized pattern. Secretory Clara cells also line the basement membrane of the airway with ciliated, neuroendocrine, and goblet cell populations (Bertoncello & McQualter, 2013). Lung cell-type terminology is undergoing a transition as the name Clara cell is being replaced by club cell; this review will use the historic term Clara cell. Neuroendocrine cells are present individually as well as in clusters termed neuroendocrine bodies that may play a role in sensing stimuli within the airway lumen (Van Lommel, 2001). Terminal bronchioles lead to the distal alveolar space containing surfactant-producing alveolar type II (AT2) cells and gas-exchanging alveolar type I (AT1) cells (Rock & Hogan, 2011).
Diverse experimental approaches have provided evidence that different populations of lung stem/progenitor cells reside in distinct niches and act in region-specific homeostasis and injury repair. Murine mouse models of injury have been utilized to study stem cells because of the low baseline levels of lung cell turnover during homeostasis and the increased rate of proliferation to replace ablated tissue following injury (Rawlins & Hogan, 2006). For example, bleomycin injures the alveolar epithelium, and naphthalene specifically injures the bronchiolar epithelium (Rawlins & Hogan, 2006). For more proximal airway injury, sulfur dioxide inhalation damages the tracheal epithelium (Borthwick, Shahbazian, Krantz, Dorin, & Randell, 2001), while ozone and nitrogen dioxide damage airway epithelial cells (Evans et al., 1976, Evans et al., 1986). Using these region-specific epithelial injury mouse models, it is possible to study cellular proliferation and epithelial regeneration. Lineage tracing is another valuable in vivo tool that has been used to study stem cell populations and their role in lung injury and repair without removing them from the lung (Raiser et al., 2008, Barkauskas et al., 2013, Rawlins, Okubo, et al., 2009, Rock et al., 2011, Tropea et al., 2012). Investigators have created mouse models to label stem cell populations of choice, which coupled with the injuries mentioned earlier, allow for detection of the lineage label, which will remain in both the progenitor population and progeny cells after injury repair.
Three-dimensional (3D) culture systems have emerged as an important method of characterizing lung stem cell properties including proliferation, differentiation, and self-renewal (Lee et al., 2012, McQualter et al., 2010, Rock et al., 2009). Fluorescence-activated cell sorting (FACS) can be used to isolate individual stem cell populations (Kim et al., 2005, Lee et al., 2013, McQualter et al., 2009, Rock et al., 2009, Summer et al., 2007, Teisanu et al., 2009, Zacharek et al., 2011), which can then be grown in clonal 3D assays in the presence of various microenvironmental factors such as Matrigel, nonepithelial cells, and growth factors to assess growth and differentiation properties. An ongoing challenge has been the ability to directly compare the functions of FACS-isolated lung stem cell populations with reparative cells in situ. Limited knowledge of markers distinguishing lung cell types in vivo has prevented precise concordance between the identity of lung cells with stem cell functions in vitro and in vivo. Transplantation assays have also been lacking in lung stem cell biology; currently there is no in vivo transplant assay for freshly sorted stem cells delivered to the lung. Recently, a kidney capsule transplantation model has been utilized as an alternative in vivo method of examining stem cell autonomous properties (Chapman et al., 2011). Subcutaneous injection of multipotent lung cells with Matrigel and the use of ex vivo decellularized lung models have also provided a new means to assess potential progenitor cell function (Longmire et al., 2012, Mou et al., 2012). The development of in vivo or in vitro assays to interrogate the function of stem cells at the single cell level, and the discovery of unique marker sets (rather than single markers) for each lung cell type are critical advances necessary to better identify lung stem cell populations and understand their relative contributions to tissue maintenance and repair.
The pathology of devastating lung diseases including lung cancers, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), asthma, bronchopulmonary dysplasia (BPD), and others is likely caused, in part, by dysregulation and dysfunction of lung stem cells. Investigators continue to work to unlock the mystery of the lung stem cell landscape by first identifying the stem cell populations, examining their cell autonomous properties, and trying to better understand their microenvironmental interactions. While much progress has been made over recent years, important questions remain and the complete picture remains unclear. Lung stem cell studies offer a new avenue for developing treatment strategies for lung disease. In this review, we discuss the current knowledge of the lung stem field and the assays and tools used to dissect the complex biology of the lung in homeostasis and disease.
Section snippets
Endogenous Lung Stem and Progenitor Cells
Endogenous adult lung stem/progenitor cells are regenerative cell populations important for epithelial cell maintenance and injury repair. In multiple adult organs, tissue-specific stem cells have been identified as multipotent cells with the capacity for long-term self-renewal and the ability to give rise to at least two distinct differentiated lineages. Tissue-specific stem cells are typically quiescent in normal conditions and proliferate during injury repair (Kolios and Moodley, 2013,
The Others: Lung Mesenchymal Stromal Cells and Lung Endothelial Progenitor Cells
Evidence continues to support the idea that adult mesenchymal stromal cells (MSCs) are an important element of epithelial stem/progenitor niches. Critical for regional specification of embryonic lung epithelium, MSCs at the distal tip of the branching epithelium are known to secrete FGF10, a critical component of the signaling network involving Bmp, Wnt, and sonic hedgehog pathways that is necessary for coordinating differentiation in the developing lung (Morrisey & Hogan, 2010). FGF10-positive
Directing Differentiation: Embryonic Stem Cells and Induced Pluripotent Stem Cells
Pluripotent embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells) hold great promise for regeneration of injured tissue and repair of disease states. ES cells are isolated from the inner cell mass of preimplantation blastocysts and under well-defined culture conditions, they can be maintained indefinitely in an undifferentiated state with the ability to give rise to cells of all three embryonic germ layers (Odorico, Kaufman, & Thomson, 2001). Takahashi and Yamanaka
MSCs: Potential Role of Cell-Based Therapy in Lung Disease
MSCs have been recently examined as a potential cell-based therapy for lung disease. MSCs secrete growth factors and antimicrobial peptides, have immunomodulatory properties, and exhibit low immunogenicity (Lee, Fang, Krasnodembskaya, Howard, & Matthay, 2011). MSCs can respond, migrate, and facilitate repair of damaged tissue making them an attractive candidate for both prevention and treatment of lung disease. MSCs can be isolated from a variety of human tissues including bone marrow, adipose
Stem Cells in Lung Cancer
Lung cancer is the leading cause of cancer related deaths in the United States and worldwide (Ettinger et al., 2013, Herbst et al., 2008). In the United States alone, nearly 200,000 people will be diagnosed with lung cancer in 2013, and the predicted 5-year survival rate for all patients is a dismal 15% (Ettinger et al., 2013). Evidence suggests that lung cancer may originate from neoplastic lung stem/progenitor cell populations and that certain lung tumors contain cancer stem cells (CSCs).
Future Directions
Identification and characterization of the various stem and progenitor cell populations in the lung will allow for the study of the mechanisms through which these cells are maintained and stimulated. Because the lung is an essential organ, understanding these mechanisms and exploiting them therapeutically for lung regenerative medicine holds great promise for improving public health. Research will likely focus now on identification of unique cell surface markers that can be used to enrich for
Acknowledgments
We thank members of our laboratory for their discussions and critical comments on the chapter. Work in our laboratory is supported by the Post-Doctoral Fellowship, PF-12-151-01-DMC, from the American Cancer Society (CMF), the Ikaria Advancing Newborn Medicine Grant (KTL), American Medical Association Foundation SEED Grant (KTL), 5 T32HD7466-15 (KTL), RO1 HL090136, U01 HL100402 RFA-HL-09-004, American Cancer Society Research Scholar Grant RSG-08-082-01-MGO, the V Foundation for Cancer Research,
References (129)
- et al.
Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient Metastatic Lung Tumors
Cancer Cell
(2010) - et al.
Primary tumor genotype is an important determinant in identification of lung cancer propagating cells
Cell Stem Cell
(2010) - et al.
Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung
Developmental Biology
(2006) - et al.
Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization
Cell
(2011) - et al.
Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement
Cytotherapy
(2006) - et al.
Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2
Experimental and Molecular Pathology
(1975) - et al.
An update on pharmacologic approaches to bronchopulmonary dysplasia
Seminars in Perinatology
(2013) - et al.
Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchioalveolar duct junction
The American Journal of Pathology
(2002) - et al.
Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers
Cell
(2012) - et al.
Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing
Cell
(2012)
The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies
Cancer Cell
Identification of mesenchymal stromal cells in human lung parenchyma capable of differentiating into aquaporin 5-expressing cells
Laboratory Investigation
Identification of bronchioalveolar stem cells in normal lung and lung cancer
Cell
Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection
Cell
Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells
Cell Stem Cell
Adult lung side populations have mesenchymal stem cell potential
Cytotherapy
Defects in tracheoesophageal and lung morphogenesis in Nkx2.1 (-/-) mouse embryos
Developmental Biology
Preparing for the first breath: Genetic and cellular mechanisms in lung development
Developmental Cell
Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs
Cell Stem Cell
The role of Scgb1a1 + Clara cells in the long-term maintenance and repair of lung airway, but not alveolar epithelium
Cell Stem Cell
Neuroepithelial bodies of pulmonary airways serve as a reservoir of progenitor cells capable of epithelial regeneration
The American Journal of Pathology
A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations
Cell
The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen
Laboratory Investigation
Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis
PLoS One
Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease
American Journal of Respiratory and Critical Care Medicine
Morphologic and biochemical study of pulmonary changes induced by bleomycin in mice
Laboratory Investigation
Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction
American Journal of Physiology. Heart and Circulatory Physiology
Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice
American Journal of Physiology. Lung Cellular and Molecular Physiology
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Nature
Type 2 alveolar cells are stem cells in adult lung
The Journal of Clinical Investigation
SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas
Nature Genetics
Ovalbumin sensitization and challenge increases the number of lung cells possessing a mesenchymal stromal cell phenotype
Respiratory Research
Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment
Proceedings of the National Academy of Sciences
Lung stem cells: Do they exist?
Respirology
Evidence for stem-cell niches in the tracheal epithelium
American Journal of Respiratory Cell and Molecular Biology
Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice
The Journal of Clinical Investigation
Stem cells: A unifying theory for the crypt
Nature
Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulation
Angiogenesis
Identification and expansion of the tumorigenic lung cancer stem cell population
Cell Death Differ
Non-small cell lung cancer, version 2.2013
Journal of the National Comprehensive Cancer Network
Role of the Clara cell in renewal of the bronchiolar epithelium
Laboratory Investigation
Renewal of the terminal bronchiolar epithelium in the rat following exposure to NO2 or O3
Laboratory Investigation
Role of nonciliated cells in renewal of the bronchial epithelium of rats exposed to NO2
The American Journal of Pathology
Well-differentiated human airway epithelial cell cultures
Methods in Molecular Medicine
Lung cancer cell lines as tools for biomedical discovery and research
Journal of the National Cancer Institute
From the laboratory bench to the patient's bedside: An update on clinical trials with mesenchymal stem cells
Journal of Cellular Physiology
Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells
Nature Biotechnology
Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice
The Journal of Immunology
Novel stem/progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential
Stem Cells
Repair and regeneration of tracheal surface epithelium and submucosal glands in a mouse model of hypoxic-ischemic injury
Respirology
Cited by (0)
- 1
These authors contributed equally