Horizontal Basal Cells Are Multipotent Progenitors in Normal and Injured Adult Olfactory Epithelium

Iwai, Naoharu; Zhou, Zhijian; Roop, Dennis R.; Behringer, Richard R.

doi:10.1634/stemcells.2007-0891

Cited by 156 publications

(129 citation statements)

References 40 publications

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“…Recent studies of adult olfactory and oral mucosae reveal that the lamina propria within these tissues are a source of mesenchymal stem cells with extensive differentiation potential [24,[36][37][38]. The olfactory mucosa also contains neural stem cells, situated within the olfactory epithelium, maintaining a lifelong turnover of olfactory receptor neurons [39]. Our in vitro characterization of the olfactory stem cells used in this study suggests that these cells are mesenchymal stem cells.…”

Section: Discussionmentioning

confidence: 66%

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

et al. 2011

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Transplantation of exogenous stem cells has been proposed as a treatment to prevent or reverse sensorineural hearing loss. Here, we investigate the effects of transplantation of adult human olfactory mucosa-derived stem cells on auditory function in A/J mice, a strain exhibiting early-onset progressive sensorineural hearing loss. Recent evidence indicates that these stem cells exhibit multipotency in transplantation settings and may represent a subtype of mesenchymal stem cell. Olfactory stem cells were injected into the cochleae of A/J mice via a lateral wall cochleostomy during the time period in which hearing loss first becomes apparent. Changes in auditory function were assessed 1 month after transplantation and compared against animals that received sham injections. Hearing threshold levels in stem cell-transplanted mice were found to be significantly lower than those of sham-injected mice (p < .05) for both click and pure tone stimuli. Transplanted cells survived within the perilymphatic compartments but did not integrate into cochlear tissues. These results indicate that transplantation of adult human olfactory mucosa-derived stem cells can help preserve auditory function during early-onset progressive sensorineural hearing loss. STEM CELLS 2011;29:670-677 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionmentioning

confidence: 66%

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

et al. 2011

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“…One study that traced HBC lineage after injury reported that HBCs remain dormant after the selective loss of mature neurons that follows olfactory bulbectomy (OBX) (9). However, the same kind of injury produced a different result in animals bearing a leaky RU486-responsive CrePR transgene driven by a Krt5 promoter (12). In the latter paradigm, some HBCs were apparently activated to multipotency following OBX.…”

Section: Resultsmentioning

confidence: 99%

“…However, as a consequence of severe tissue injury and the wholesale loss of both neurons and sustentacular (Sus) cells, HBCs lose their attachment to the basal lamina, proliferate, transition into GBCs, and give rise to all types of cellular constituents of the OE during its regeneration, a constellation of responses that we term "activation" (9)(10)(11). In contrast, existing data suggest that selective neuronal loss in response to ablation of the olfactory bulb does not result in HBC activation (9), although another laboratory has observed an enhanced HBC contribution to the epithelium after bulb ablation (12). The effect of the targeted death of Sus cells has not been investigated.…”

mentioning

confidence: 94%

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

Herrick

Lin

Peterson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The remarkable capacity of the adult olfactory epithelium (OE) to regenerate fully both neurosensory and nonneuronal cell types after severe epithelial injury depends on life-long persistence of two stem cell populations: the horizontal basal cells (HBCs), which are quiescent and held in reserve, and mitotically active globose basal cells. It has recently been demonstrated that down-regulation of the ΔN form of the transcription factor p63 is both necessary and sufficient to release HBCs from dormancy. However, the mechanisms by which p63 is down-regulated after acute OE injury remain unknown. To identify the cellular source of potential signaling mechanisms, we assessed HBC activation after neuron-only and sustentacular cell death. We found that ablation of sustentacular cells is sufficient for HBC activation to multipotency. By expression analysis, nextgeneration sequencing, and immunohistochemical examination, down-regulation of Notch pathway signaling is coincident with HBC activation. Therefore, using HBC-specific conditional knockout of Notch receptors and overexpression of N1ICD, we show that Notch signaling maintains p63 levels and HBC dormancy, in contrast to its suppression of p63 expression in other tissues. Additionally, Notch1, but not Notch2, is required to maintain HBC dormancy after selective neuronal degeneration. Taken together, our data indicate that the activation of HBCs observed after tissue injury or sustentacular cell ablation is caused by the reduction/elimination of Notch signaling on HBCs; elimination of Jagged1 expressed by sustentacular cells may be the ligand responsible.Notch | olfactory epithelium | reserve stem cell | trp63

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“…HBCs express the epithelial markers keratin 5 (K5) and CD54 (also known as ICAM-1), and HBCs express the stem cell markers Pax6 and Sox2 [5][6][7][8]. Although the evidence collected to date is far from conclusive, it has been suggested that HBCs are the tissue stem cells in the OE because HBCs can self-renew and generate neuronal and non-neuronal cells, including the GBCs, in vivo (both during normal turnover and following OE injury) as well as in vitro [4,[9][10][11]. HBCs express the transcription factor p63, which is essential for the proliferation of epithelial stem cells that give rise to the thymus and epidermis [12].…”

Section: Introductionmentioning

confidence: 99%

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

Suzuki

Sakurai

Yamazaki

et al. 2015

Stem Cells and Development

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In the mammalian olfactory epithelium (OE), olfactory receptor neurons (ORNs) are continuously regenerated throughout the animal's lifetime. Horizontal basal cells (HBCs) in the OE express the epithelial marker keratin 5 (K5) and the stem cell marker Pax6 and are considered relatively quiescent tissue stem cells in the OE. Pax6 is a key regulator of several developmental processes in the central nervous system and in sensory organs. Although Pax6 is expressed in the OE, its precise role remains unknown, particularly with respect to stem celllike HBCs. To investigate the function of Pax6 in the developmental and regenerative processes in the OE, we generated conditional Pax6-knockout mice carrying a loxP-floxed Pax6 gene. Homozygous Pax6-floxed mice were crossed with K5-Cre transgenic mice to generate HBC-specific Pax6-knockout (Pax6-cKO) mice. We confirmed that the deletion of Pax6 expression in HBCs was sufficiently achieved in zone 1 of the OE in Pax6-cKO mice 3 days after methimazole-induced severe damage. In this condition, regeneration of the OE was dramatically impaired; both OE thickness and the number of ORNs were significantly decreased in the regenerated OE of Pax6-cKO mice. These results suggest that Pax6 expression is essential for HBCs to differentiate into neuronal cells during the regeneration process following severe injury.

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Horizontal Basal Cells Are Multipotent Progenitors in Normal and Injured Adult Olfactory Epithelium

Cited by 156 publications

References 40 publications

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

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

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

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