Figure 7.

Model of the lineage hierarchy for the developing airway submucosal gland. (A) Stem cells of the primordial gland placode express basal cell markers (CK5, CK14, p63), but lack myoepithelial cell (MEC) markers (αSMA and SMMHC). Two transcription factors, lymphoid enhancer binding factor-1 (Lef-1) and SRY-box 9 (Sox9), are also highly expressed in the stem cells of the primordial gland placode. (B) During the elongation phase, the first lineage-positive MECs (αSMA⁺, SMMHC⁺) emerge at the tips of the elongating tubules. Lineage tracing studies suggest that the MECs born during the 3–7-day window after birth are multipotent and retain Lef-1 and Sox9 expression, as well as other basal cell phenotypes (CK5⁺, CK14⁺, and p63⁺). However, these data also support the existence of a second lineage-negative progenitor (i.e., not of MEC lineage, αSMA⁻, SMMHC⁻) that contributes cells to the developing SMG. These lineage-negative progenitors likely also express Lef-1 and Sox9, as nearly all cells of the tubule express these transcription factors at this stage. However, because expression of basal cell markers during the elongation phase is not uniform, it is unclear whether lineage-negative progenitors express CK5 and/or CK14. (C) During branching and differentiation phases of SMG development, multipotent MECs can give rise to new MECs and differentiate into serous cells, mucous cells, and ductal cells. Although the lineage hierarchy of MEC progenitors remains unclear, timed pulse induction studies after birth suggest that both multipotent and unipotent MECs likely exist. Lineage-negative progenitors appear to have a lineage bias for differentiation into ductal cells and mucous cells, but less frequently differentiate into serous cells and MECs. The inverted triangles schematically show the relative lineage bias for differentiation of each progenitor population (red, most abundant; blue, least abundant). (D) Differentiation markers used in this study to define various cell types.