Canonical Wnt signaling promotes the proliferation and neurogenesis of peripheral olfactory stem cells during postnatal development and adult regeneration

Wang, Ya Zhou; Yamagami, Takashi; Gan, Qini; Wang, Yongping; Zhao, Tianyu; Hamad, Salaheddin; Lott, Paul; Schnittke, Nikolai; Schwob, James E.; Zhou, Chengji J.

doi:10.1242/jcs.080580

Cited by 55 publications

(53 citation statements)

References 75 publications

(86 reference statements)

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“…Interestingly, the loss of OSNs observed in the developing OE was regional, whereas in the recovering OE it was global. We speculate that these differences can be attributed to the temporal and spatial release of morphogens during development that are synchronized after severe injury to the OE (Vedin et al, 2009). Nevertheless, our data demonstrate a clear role for HBCs and their cilia in the developing OE.…”

Section: Discussionmentioning

confidence: 97%

Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium

et al. 2015

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The olfactory epithelium (OE) is one of the few tissues to undergo constitutive neurogenesis throughout the mammalian lifespan. It is composed of multiple cell types including olfactory sensory neurons (OSNs) that are readily replaced by two populations of basal stem cells, frequently dividing globose basal cells and quiescent horizontal basal cells (HBCs). However, the precise mechanisms by which these cells mediate OE regeneration are unclear. Here, we show for the first time that the HBC subpopulation of basal stem cells uniquely possesses primary cilia that are aligned in an apical orientation in direct apposition to sustentacular cell end feet. The positioning of these cilia suggests that they function in the detection of growth signals and/or differentiation cues. To test this idea, we generated an inducible, cell type-specific Ift88 knock-out mouse line (K5rtTA;tetOCre;Ift88 fl/fl ) to disrupt cilia formation and maintenance specifically in HBCs. Surprisingly, the loss of HBC cilia did not affect the maintenance of the adult OE but dramatically impaired the regeneration of OSNs following lesion. Furthermore, the loss of cilia during development resulted in a region-specific decrease in neurogenesis, implicating HBCs in the establishment of the OE. Together, these results suggest a novel role for primary cilia in HBC activation, proliferation, and differentiation.

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Section: Discussionmentioning

confidence: 97%

Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium

et al. 2015

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“…Previous investigations regarding OE basal cell regulation suggest overlap with other well-characterized stem cell niches. Mechanisms informing basal cells of epithelial status or controlling cell cycle or lineage decisions are likely to include Lgr5 and Wnt signaling, TGFβ superfamily signaling, c-Kit, p63, the Notch pathway and basic helix-loop-helix (bHLH) factors Fletcher et al, 2011;Gokoffski et al, 2011;Goldstein et al, 2015;Guillemot et al, 1993;Guo et al, 2010;Schnittke et al, 2015;Wang et al, 2011). Nonetheless, regulation of OE homeostasis, and strategies for correction of failures in this process leading to olfactory dysfunction, remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Contribution of Polycomb group proteins to olfactory basal stem cell self-renewal in a novel c-KIT+ culture model and in vivo

et al. 2016

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Olfactory epithelium (OE) has a lifelong capacity for neurogenesis due to the presence of basal stem cells. Despite the ability to generate short-term cultures, the successful in vitro expansion of purified stem cells from adult OE has not been reported. We sought to establish expansion-competent OE stem cell cultures to facilitate further study of the mechanisms and cell populations important in OE renewal. Successful cultures were prepared using adult mouse basal cells selected for expression of c-KIT. We show that c-KIT signaling regulates self-renewal capacity and prevents neurodifferentiation in culture. Inhibition of TGFβ family signaling, a known negative regulator of embryonic basal cells, is also necessary for maintenance of the proliferative, undifferentiated state in vitro. Characterizing successful cultures, we identified expression of BMI1 and other Polycomb proteins not previously identified in olfactory basal cells but known to be essential for self-renewal in other stem cell populations. Inducible fate mapping demonstrates that BMI1 is expressed in vivo by multipotent OE progenitors, validating our culture model. These findings provide mechanistic insights into the renewal and potency of olfactory stem cells.

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“…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).…”

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confidence: 99%

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

Chen

Reed

Lane

2017

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

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Adult neural stem cells/progenitor cells residing in the basal layer of the olfactory epithelium are capable of reconstituting the neuroepithelium even after severe damage. The molecular events underlying this regenerative capacity remain elusive. Here we show that the repair of neuroepithelium after lesioning is accompanied by an acute, but self-limited, inflammatory process. Attenuation of inflammatory cell recruitment and cytokine production by dexamethasone impairs proliferation of progenitor horizontal basal cells (HBCs) and subsequent neuronal differentiation. Using TNF-α receptor-deficient mice, we identify TNF-α signaling as an important contributor to this inflammatory and reparative process, mainly through TNF-α receptor 1. HBC-selective genetic ablation of RelA (p65), the transcriptional activator of the NF-κB pathway, retards inflammation and impedes proliferation at the early stages of regeneration and suggests HBCs directly participate in cross-talk between immune response and neurogenesis. Loss of RelA in the regenerating neuroepithelium perturbs the homeostasis between proliferation and apoptosis while enhancing JNK signaling. Together, our results support a model in which acute inflammation after injury initiates important regenerative signals in part through NF-κB-mediated signaling that activates neural stem cells to reconstitute the olfactory epithelium.neuroregeneration | inflammation | olfactory stem cells | NF-κB

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Canonical Wnt signaling promotes the proliferation and neurogenesis of peripheral olfactory stem cells during postnatal development and adult regeneration

Cited by 55 publications

References 75 publications

Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium

Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium

Contribution of Polycomb group proteins to olfactory basal stem cell self-renewal in a novel c-KIT+ culture model and in vivo

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

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