Lung Stem and Progenitor Cells in Tissue Homeostasis and Disease

Abstract

The mammalian lung is a complex organ containing numerous putative stem/progenitor cell populations that contribute to region-specific tissue homeostasis and repair. In this review, we discuss recent advances in identifying and studying these cell populations in the context of lung homeostasis and disease. Genetically engineered mice now allow for lineage tracing of several lung stem and progenitor cell populations in vivo during different types of lung injury repair. Using specific sets of cell surface markers, these cells can also be isolated from murine and human lung and tested in 3D culture systems and in vivo transplant assays. The pathology of devastating lung diseases, including lung cancers, is likely in part due to dysregulation and dysfunction of lung stem cells. More precise characterization of stem cells with identification of new, unique markers; improvement in isolation and transplant techniques; and further development of functional assays will ultimately lead to new therapies for a host of human lung diseases. In particular, lung cancer biology may be greatly informed by findings in normal lung stem cell biology as evidence suggests that lung cancer is a disease that begins in, and may be driven by, neoplastic lung stem cells.

Influenza virus-induced lung injury: pathogenesis and implications for treatment

“…These include populations of airway basal cells expressing p63 and keratin 5, subsets of club cells in the distal airways including itgb4 + CD24 low cells, and putative populations of bronchoalveolar stem cells at the bronchoalveolar duct junction. Within the alveoli, itgb4 + cells, "bipotent" type I and type II alveolar epithelial cell progenitors and alveolar type II cells have been attributed stem/progenitor cell functions during repair [158,159]. While all of these populations have been reported to expand in different models of lung injury, the emergence of p63-positive and keratin 5-positive epithelial pods in the alveolar space has only been observed after severe IAV-induced lung injury [160,161].…”

“…Whether this is accompanied by expansion of other progenitor pools or whether direct or immune-mediated damage to the more distal progenitor populations in response to viral infection necessitates the expansion of the airway stem cell pool is not known. Soluble growth factors involved in these responses comprise, among others, fibroblast growth factors, EGFs, HGFs, and transforming growth factor-β [158], some of which are induced in IAV infection [150,154,162,163]. Our own data reveal that a itgb4 + progenitor cell population is crucial for bronchial and alveolar repair after IAV-induced lung injury in mice, a process involving cross-talk with resident mesenchymal niche cells, extracellular matrix laminins and FGF10 (S. Herold and G.R.S.…”

Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation

“…The tracheobronchial tree is lined by a diversity of epithelial cells including basal, ciliated, serous, and goblet cells that make unique contributions to mucociliary clearance, innate immunity, and recruitment and activation of professional immune cells that mediate inflammatory responses to environmental exposures (1)(2)(3)(4)(5). The nature and extent of innate and acquired immune responses to respiratory pathogens and allergens are influenced genetically and developmentally and by exposure to specific pathogens and toxicants.…”

An Official American Thoracic Society Workshop Report: Stem Cells and Cell Therapies in Lung Biology and Diseases

“…Despite suggested guidelines from previous conferences and from other sources, precise definitions and characterizations of specific cell populations, notably the putative endogenous cell populations in the lung as well as MSCs and EPCs, are not agreed on. In many respects this reflects more sophisticated knowledge and increasing appreciation that the phenotypic and functional attributes of cells are context dependent (12)(13)(14)(15)(16)(17)(18)(19). Cells previously considered to be differentiated airway or alveolar epithelial cells can proliferate and differentiate into other lung epithelial cell types under varying circumstances.…”

“…Significant progress also continues to be made in investigations of local (endogenous) stem and progenitor cells resident in adult lungs. Advances in lineage tracing approaches and other techniques continue to provide important insights into understanding of the identity and lineage expansion properties of previously identified putative endogenous stem and progenitor populations and suggest an increasingly complex network of cellular repair after injury (reviewed in [12][13][14][15][16][17][18][19]). Recent data have broadened this beyond consideration of epithelial progenitors to also include endogenous pulmonary vascular and interstitial progenitors (20)(21)(22).…”