Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license

Abstract

The capacity of the olfactory epithelium (OE) for lifelong neurogenesis and regeneration depends on the persistence of neurocompetent stem cells, which self-renew as well as generating all of the cell types found within the nasal epithelium. This Review focuses on the types of stem and progenitor cells in the epithelium and their regulation. Both horizontal basal cells (HBCs) and some among the population of globose basal cells (GBCs) are stem cells, but the two types plays vastly different roles. The GBC population includes the basal cells that proliferate in the uninjured OE and is heterogeneous with respect to transcription factor expression. From upstream in the hierarchy to downstream, GBCs encompass 1) Sox2+/Pax6+ stem-like cells that are totipotent and self-renew over the long term, 2) Ascl1+ transit-amplifying progenitors with a limited capacity for expansive proliferation, and 3) Neurog1+/NeuroD1+ immediate precursor cells that make neurons directly. In contrast, the normally quiescent HBCs are activated to multipotency and proliferate when sustentacular cells are killed, but not when only OSNs die, indicating that HBCs are reserve stem cells that respond to severe epithelial injury. The master regulator of HBC activation is the ΔN isoform of the transcription factor p63; eliminating ΔNp63 unleashes HBC multipotency. Notch signaling, via Jagged1 ligand on Sus cells and Notch1 and Notch2 receptors on HBCs, is likely to play a major role in setting the level of p63 expression. Thus, ΔNp63 becomes a potential therapeutic target for reversing the neurogenic exhaustion characteristic of the aged OE.

Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency

“…Transplantation of olfactory epithelial stem and progenitor cells has proven to be a sensitive and effective method for assaying and understanding the regulation of differentiative potency (Reviewed in Schwob et al 2017). For example, HBC stem cells must experience the effects of epithelial damage in situ prior to isolation and transplantation in order to evince active multipotency even when engrafted into the MeBr-lesioned OE (Schnittke et al, 2015).…”

“…Previous observations by our lab and many others demonstrate an apparently hierarchical and unidirectional progression of progenitor types culminating in the birth and differentiation of neurons and also non-neuronal cells when epithelial repair requires them as well. At the apex of that hierarchy are two multipotent stem cell populations: reserve horizontal basal cells (HBCs) and active globose basal cells (GBCs) (Chen et al, 2004; Guo et al, 2010; Huard et al, 1998; Leung et al, 2007; Schnittke et al, 2015; Reviewed in Schwob et al 2017) (Fig. 1A-B).…”

Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell

“…Nonetheless, our findings also have significant implications for the aging of the OE and olfactory dysfunction in the elderly. Despite the remarkable capacity for lifelong neurogenesis in the OE, we have previously demonstrated in both humans and mice that the aged OE has areas of aneuronal tissue, where the active GBC population has been exhausted and neurogenesis has ceased (67)(68)(69). However, the HBCs in this setting remain dormant and fail to regenerate the functional neuronal tissue, perhaps because Sus cells remain intact.…”

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

“…neuroregeneration | inflammation | olfactory stem cells | NF-κB I n the olfactory epithelium (OE), mitotically active globose basal cells (GBCs) continuously replenish olfactory sensory neurons (OSNs) lost throughout life (1)(2)(3). Wnt signaling (3,4) and expression of transcription factors including Ascl1 (Mash1), Ngn1, and NeuroD1 (1,5) contribute to cell fate determination and differentiation of GBCs.…”

“…Wnt signaling (3,4) and expression of transcription factors including Ascl1 (Mash1), Ngn1, and NeuroD1 (1,5) contribute to cell fate determination and differentiation of GBCs. Horizontal basal cells (HBCs) serve as a reserve stem cell pool that is largely quiescent but becomes a major contributor after severe injury (6).…”