Figure 5.

p63 Is the master regulator of the formation and activation–dormancy of the HBCs, the second category of OE stem cells, which are held in reserve normally. HBCs are formed from basally migrating olfactory placodal precursors (OPP) when ΔNp63 is upregulated during perinatal development (Packard et al., 2011b). In the absence of direct epithelial damage, HBCs are dormant (mitotically quiescent and nonparticipatory in the generation of replacement neurons; Huard and Schwob, 1995; Leung et al., 2007). With injury, ΔNp63 levels decline, and many of the HBCs differentiate into GBCs, which in turn give rise to neurons and other epithelial cell types (Packard et al., 2011b; Fletcher et al., 2011; Schnittke et al., 2015). The suggestion that HBCs may directly give rise to other cell types following injury is indicated by the upward-pointing arrow (Schwob et al., 1995). During epithelial repair, GBCs that initiate ΔNp63 expression in response to local cues or as a consequence of retroviral transduction give rise to HBCs, which return to quiescence (Schnittke et al., 2015). Genetic excision of ΔNp63 activates HBCs, generates GBCs that remain active for more than 6 months indicating stem cell capacity, and simultaneously prevents the regeneration of HBCs from GBCs bearing the mutated gene (Schnittke et al., 2015). Thus, expression of ΔNp63 is both necessary and sufficient for the formation of HBCs, and conversely downregulation of ΔNp63 is both necessary and sufficient for HBCs to activate. As a result of very severe injury, in which the population of GBCs and possibly gland/duct cells is completely depleted, the activated HBCs contribute to respiratory metaplasia, i.e., give rise to ciliated columnar cells like those found in respiratory epithelium (RE; red profiles between HBC and basal lamina represent olfactory axons; Xie et al., 2013).