The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells.

The conducting airways (bronchi and bronchioles) and peripheral gas exchange (alveolar) regions of the mammalian lung are generated by a process of branching morphogenesis. Evidence suggests that during embryonic development, the undifferentiated epithelial progenitors are located at the distal tips of the branching epithelium. To test this hypothesis, we used an Id2-CreER(T2) knock-in mouse strain to lineage trace the distal epithelial tip cells during either the pseudoglandular or canalicular phases of development. During the pseudoglandular stage, the tip cells both self-renew and contribute descendents to all epithelial cell lineages, including neuroendocrine cells. In addition, individual Id2(+) tip cells can self-renew and contribute descendents to both the bronchiolar and alveolar compartments. By contrast, during the later canalicular stage, the distal epithelial tip cells only contribute descendents to the alveoli. Taken together, this evidence supports a model in which the distal tip of the developing lung contains a multipotent epithelial population, the fate of which changes during development.

Basal cells as stem cells of the mouse trachea and human airway epithelium.

The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreER(T2) transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.

A 10-gene progenitor cell signature predicts poor prognosis in lung adenocarcinoma.

BACKGROUND: One aspect of the cancer stem cell hypothesis is that patients with tumors that exhibit stem-like phenotypes have poor prognoses. Distal epithelial progenitors from lungs early in development demonstrate both self-renewal and potential to differentiate into all bronchial and alveolar epithelial cell types. By contrast, late progenitors are only able to produce alveolar cells. We sought to create a lung-specific progenitor cell signature for possible prognosis prediction in human lung cancer. METHODS: A transgenic mouse was created in which embryonic distal epithelial progenitor cells express green fluorescent protein when tamoxifen is administered. Lung progenitor cells were harvested after tamoxifen injection at either embryonic day 11.5 (E11.5) or 17.5 (E17.5). The RNA extracted from these cells was hybridized to Affymetrix 430.2 mouse chips (Affymetrix, Santa Clara, CA). A genomic signature was created by comparing the cell types using L1 logistic regression and applied to transcriptome datasets of resected patients from our tumor bank and the National Institutes of Health Director's Challenge Consortium. RESULTS: When a 10-gene genomic signature was applied to resected human adenocarcinoma datasets, tumors that were transcriptionally similar to the early progenitors had a significantly worse prognosis than those similar to the late progenitors. Using a Cox model in which age and stage were included, the predicted score from the logistic regression model was an independent predictor of survival. CONCLUSIONS: A lung progenitor cell signature predicts poor prognosis in lung adenocarcinoma. Modulation of these genes or their signaling pathways may be effective therapeutic strategies in the future.