Maintenance, differentiation and regulation of multipotent progenitor cells in the olfactory epithelium

The presence of multipotent progenitor cells (MPPs) and stem cells in the olfactory epithelium (OE) has been demonstrated by numerous clinical and experimental observations. Among the OE cells, globose basal cells (GBCs) are a heterogeneous population, and some are multipotent. In this study, we identified GBCs that express both Sox2 and Pax6, known to regulate multipotent progenitors elsewhere. In addition, Pax6 and Sox2 are found in horizontal basal cells (HBCs) and sustentacular cells (Sus). The in-depth characterization of these Pax6/Sox2 (+) GBCs in the normal OE indicate that these GBCs include quiescent, undifferentiated cells, and cells that are committed to making neurons but are not yet giving rise to them. The expression dynamics of Pax6 and Sox2 in the regenerating OE after MeBr lesion and after bulbectomy further confirm the pattern of Pax6/Sox2 expression in the MPPs and early neuronal progenitors. In future, Sox2, Pax6 and the cell cycle inhibitor p27 may be used to mark and isolate the quiescent MPPs/stem cells in the OE.; We then studied the role of Notch signaling in cell fate choice in the OE. We find that Notch1 is expressed by a subset of the GBCs in the adult OE and the Notch1 (+) cells are most likely upstream of a commitment to neuron production. Loss-of-function and gain-of-function manipulations of Notch signaling indicate that Notch signaling is required in sustentacular (Sus) cell differentiation and functions as a cell fate switch between Sus cell fate and neuronal fate in the MPPs, since Notch signaling favors Sus cell fate when both cell fates are available, e.g. in the multipotent GBCs activated by MeBr lesion. However, Notch signaling alone is not sufficient to drive Sus cell differentiation in a neurogenic environment, e.g. in the OE after bulbectomy; or in cells that are not immediately primed to make Sus cells, e.g. duct/gland cells after MeBr lesion. Therefore, the role of Notch signaling in Sus cell differentiation is more likely permissive than instructive. Furthermore, Notch signaling is also temporally regulated and cell context dependent in the OE.