Basal Cells Are a Multipotent Progenitor Capable of Renewing the Bronchial Epithelium

Abstract

Commitment of the pulmonary epithelium to bronchial and bronchiolar airway lineages occurs during the transition from pseudoglandular to cannalicular phases of lung development, suggesting that regional differences exist with respect to the identity of stem and progenitor cells that contribute to epithelial maintenance in adulthood. We previously defined a critical role for Clara cell secretory protein-expressing (CE) cells in renewal of bronchiolar airway epithelium following injury. Even though CE cells are also the principal progenitor for maintenance of the bronchial airway epithelium, CE cell injury is resolved through a mechanism involving recruitment of a second progenitor cell population that we now identify as a GSI-B 4 reactive, cytokeratin-14-expressing basal cell. These cells exhibit multipotent differentiation capacity as assessed by analysis of cellular phenotype within clones of LacZ-tagged cells. Clones were derived from K14-expressing cells tagged in a cell-type-specific fashion by ligand-regulable Cre recombinase-mediated genomic rearrangement of the ROSA26 recombination substrate allele. We conclude that basal cells represent an alternative multipotent progenitor cell population of bronchial airways and that progenitor cell selection is dictated by the type of airway injury. Conducting airways of the lung are lined by a highly specialized epithelium whose composition and function varies along the proximal to distal axis. Despite a growing appreciation of mechanisms contributing to branching morphogenesis and lineage specification in the developing lung it is still unclear how a complex epithelium such as that present in the conducting airway is established and maintained through adulthood. Studies in the developing rat lung indicate that lineage restriction occurs during the transition from the pseudoglandular to cannalicular phases of lung development. At this time cells of the proximal airway lose the ability to respond to mesenchymally derived signals capable of inducing distal airway differentiation.

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

“…Differences in CYP450 enzymatic activity, cellular glutathione pool size, and glutathione regenerative capacity further distinguish these cells and may contribute to variation in pollutant sensitivity (14,17,34,37,55,56). The local stem cells that repopulate the airway epithelium also differ between proximal and distal airways (18,23). Progenitor cells with the potential to contribute to airway repair include secretory, neuroendocrine, and basal cell populations.…”

“…The individual contributions of each progenitor cell may depend on the nature of the injury. However, it is noteworthy that basal cells only exist in the proximal airway and thus can only contribute to proximal airway epithelial repair, whereas local stem cells for distal airway cells include so-called variant Clara cells, cells that express CCSP but not CYP-2F2 (22,23,41). Finally, it is known that the proximal but not distal secretory cells undergo mucus metaplasia in response to allergic inflammation, whereas distal cells undergo relatively more proliferation under the same stimulus (16,40).…”

CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

“…All procedures were approved by the Institutional Animal Care and Use Committee at the University of Nice-Sophia Antipolis, Nice, France. CD98hc conditional null mice, CD98hc fl/fl (Féral et al, 2007), were crossed with K14-CreER T2 transgenic mice (gift of B. Stripp, Duke University Medical Center, Durham, NC; Hong et al, 2004). Mixed background C57BL/ 6-svJ129 K14CreER T2 ; CD98hc fl/fl mice have been backcrossed seven times onto the C57BL/6 backgrounds.…”

Attributes of adult stem cells

“…Progress in identifying lung stem cells has been impeded by the slow turnover of airway and alveolar epithelium, but the consensus view is that there is no single multipotential stem cell for the lung, but rather there are regiospecific stem cell zones in the proximal and distal lung [156, [157]. In the bronchiolar epithelium, stem cell function appears to be the property of rare pollutant-resistant CE cells, co-localized with pulmonary neuroendocrine cells (PNECs), normally located in cell clusters termed neuroepithelial bodies (NEBs); PNECs can only act as progenitors for more PNECs [158].…”