Figure 1.

Epithelial progenitor cells of the embryonic lung. (A) Schematic representation of epithelial progenitor cells during early lung development. During the pseudoglandular stage (∼E10.5-16 in the mouse), the lung contains a system of actively branching epithelial tubes. Cells at the distal tip are morphologically unspecialized and are characterized by the expression of a number of genes encoding signaling proteins, transcription factors, and components of downstream signaling pathways. These include Sox9, NMyc, Id2 (Idb2), Pea3, Erm, Bmp4 (see References 25 and 31). There are numerous reciprocal interactions (red arrows) between the epithelium and the surrounding mesenchyme and vasculature that involve multiple secreted signaling factors, including sonic hedgehog, Fgfs, and Wnts (25–27). As the tips grow out and branch, they leave behind cells in the proximal stalks that give rise to differentiated cell types. Markers for these phenotypes first appear around E14.5 in the most proximal regions (32), and the process of differentiation proceeds from proximal to distal. Just before birth, the cells in the distal tips give rise to the precursors of the terminal alveoli containing type I and type II cells. It is not known how the switch in fate of the daughter cells—from proximal airway cells to alveolar cells—is regulated. (B) The distal progenitor cells rapidly transit the cell cycle so that after a 1-hour pulse of bromodeoxyuridine (BrdU) in utero at E12.5, about 80% of the distal tip cells are labeled (arrow) (29). Scale bar = 50 μm. (C) Whole mount in situ hybridization of E11.5 mouse lung shows that distal epithelial progenitor cells (arrow) preferentially express the transcription factor, Id2 (also known as Idb2). (D) Immunohistochemistry of section of E14.5 mouse lung shows that distal epithelial cells preferentially express Sox9 (arrow). In the adult lung, Sox9 expression is absent (see also Reference 33). Scale bar = 60 μm.