Fig. 6.1.

Lineage relationships of the surface airway epithelium in the trachea and bronchi. (a) Basal cells self-renew and give rise to all of the cell types present in the surface airway epithelium. Basal cells differentiate into luminal lineages through an intermediate suprabasal cell state [10]. Basal cells can give rise to self-renewing neuroendocrine cells in addition to brush (or tuft) cells and ionocytes [1, 2]. In addition, a subset of basal cells that display intracellular Notch2 activation (N2ICD) gives rise to secretory cells, whereas basal cells that express low levels of c-myb are able to lineage commit toward multiciliated cells [11]. Recent, single-cell RNA sequencing experiments have suggested that basal cells give rise to multiciliated cells through a differentiation of an intermediate population of pre-ciliated cells [12]. If basal cells are ablated, club-like cells can renew basal cells through a process of dedifferentiation (dashed line) [13]. (b) Secretory cells in large airways consist of club-like cells and goblet cells. Club-like cells are similar to bronchiolar club cells in that they express proteins commonly used to identify bronchiolar club cells, such as SCGB1A1 (a.k.a. club cell secretory protein); however, unlike bronchiolar club cells, large airway club-like cells also express mucins such as MUC5B and MUC5AC [14]. Secretory goblet cells have a distinct goblet or cup-like morphology but express many of the same phenotypic markers that club-like cells express; thus, it is unclear if club-like cells and goblet cells are distinct secretory cell fates or if a single population of secretory cells fluctuates between displaying a club-like or goblet cell morphology depending on environmental factors. Multiciliated cell renewal is primarily accomplished by club-like progenitors at steady state [10] and following injury [1, 12]. In addition, it has recently been argued that goblet cells may act as a differentiation intermediate between club-like secretory cells and multiciliated cells [12]