Olfactory epithelium: Cells, clinical disorders, and insights from an adult stem cell niche

Abstract

Disorders causing a loss of the sense of smell remain a therapeutic challenge. Basic research has, however, greatly expanded our knowledge of the organization and function of the olfactory system. This review describes advances in our understanding of the cellular components of the peripheral olfactory system, specifically the olfactory epithelium in the nose. The article discusses recent findings regarding the mechanisms involved in regeneration and cellular renewal from basal stem cells in the adult olfactory epithelium, considering the strategies involved in embryonic olfactory development and insights from research on other stem cell niches. In the context of clinical conditions causing anosmia, the current view of adult olfactory neurogenesis, tissue homeostasis, and failures in these processes is considered, along with current and future treatment strategies.

Level of evidence: NA.

Keywords: Olfaction; anosmia; regeneration; stem cells.

Figure 1

Overview of the peripheral olfactory system. Within the nasal cavity, the OE is the peripheral organ for the sense of smell. (A) While respiratory epithelium lines the majority of the nasal cavity, OE lines the region of the olfactory cleft. On a coronal CT image through the nasal region, the olfactory cleft (box) is seen in the superior medial area. (B) On closer view of the olfactory cleft, the area lined by OE (blue) is indicated. The cribriform plate bone separates nasal cavity from cranial cavity, with the olfactory bulbs and crista galli seen superior to the olfactory cleft. OE lines the medial superior vertical lamellae of the superior turbinates and the corresponding superior septum. However, there is considerable variability among individuals, with biopsy samples often showing patches of respiratory epithelium from superior olfactory cleft. (C) The composition of the OE is shown schematically. OE is a pseudostratified neuroepithelium, housing the cell bodies of mature olfactory sensory neurons (mOSN), as well as immature neurons (iOSN) produced from basal stem cells. Two populations of stem and progenitor cells, the globose basal cells (GBC) and the horizontal basal cells (HBC), support life long self‐renewal of the OE, replacing neurons as needed. Glia‐like sustentacular (Sus) and sensory microvillar (MV) cells are situated apically. Axons from OSNs exit the base of the OE and their fascicles project as the first cranial nerve (CN I) through the cribriform plate to synapse in the olfactory bulbs. At the nasal airspace, OSNs extend a mat of immobile cilia (blue) from their dendritic knobs. (D) The cilia are the site of odor transduction. Inspired odor molecules are recognized by odor receptors (OR) expressed at the neuronal cilia membranes. ORs are seven‐transmembrane domain G‐protein coupled receptors. OR activation leads to OSN depolarization and signaling to specific olfactory bulb glomeruli. BL indicates basal lamina.

Figure 2

Adult stem cells and tissue homeostasis in the olfactory epithelium (OE). The population of olfactory sensory neurons (OSNs) are inherently vulnerable to damage and death, positioned in contact with the nasal airspace. However, mammals have retained an ability to replenish OSNs, and the other cells of the OE, from populations of basal neural stem cells, the horizontal basal cells (HBCs) and globose basal cells (GBCs) described in Fig. 1. (A) A schematic depiction of injury and epithelial reconstitution in the OE. In experimental animal models, toxicants or chemical exposures lead to a rapid degeneration of the normal OE cells, generally sparing some of the basal populations post‐injury, as shown. Within days to weeks, stem cells respond to tissue injury to proliferate and produce pools of differentiating precursors, leading to OE reconstitution. As in other self‐renewing tissues, stem cells are subject to regulatory mechanisms to maintain epithelial homeostasis. (B) OE stem and progenitor cell populations produce the multiple cell lineages in the OE. Several progenitor cell stages are indicated, and are identifiable by expression of specific regulatory factors. Key transcription factors (i.e. Sox2, Ascl1, Neurog1, NeuroD, OAZ), epigenetic modifiers (Bmi1), or growth factor receptors (c‐Kit) marking specific cells are indicated. Growth factors and feedback signals, such as ActivinB, BMP4, and GDF11 are not depicted here. Intercellular signaling conveys the status of the OE to basal cells; for instance Notch‐Delta signals from the sustentacular cells to the HBCs have been shown to regulate proliferation or dormancy via p63 inactivation.