Contribution of olfactory neural stem cells to tissue maintenance and regeneration

Abstract

The olfactory neuroepithelium undergoes continual neurogenesis and, after extensive lesions, fully regenerates to maintain sensory function. The stem cell population underlying this regenerative capacity remains elusive. Here we show that mouse horizontal basal cells (HBCs) function as adult olfactory neuroepithelium neural stem cells and examine their distinct dynamics in olfactory neuroepithelium maintenance and regeneration. Fate-mapping analysis after olfactory neuroepithelium lesioning shows that HBCs are competent to regenerate both neuronal and non-neuronal olfactory neuroepithelium lineages. HBCs serve as a reservoir of long-lived progenitors that remain largely quiescent during normal neuronal turnover or even after acute, selective loss of mature neurons. Under these conditions, previously identified progenitors are largely responsible for tissue maintenance. Yet after extensive injuries that deplete resident neuronal precursors, HBCs transiently proliferate and their progeny fully reconstitute the neuroepithelium. Our data support a new model of adult neurogenesis in which distinct cell populations mediate normal neuronal turnover and neuronal replacement upon traumatic injury.

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Figure 1: Effective and specific labeling of HBCs in the olfactory neuroepithelium.
Figure 2: HBCs were quiescent and long lived.
Figure 3: HBCs generated multiple OE cell types after MeBr lesion.
Figure 4: HBCs generated neuronal and non-neuronal cell types after MeBr lesion.
Figure 5: Individual HBC-derived clones.
Figure 6: Marked HBCs gave rise to GBCs after MeBr lesion.
Figure 7: Distinct HBC responses after different injury paradigms.
Figure 8: Cellular dynamics of HBCs during regeneration.

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Acknowledgements

We appreciate the helpful suggestions of J. Nathans, P. Chambon for providing the K5-CreERT2 mice, and D. Johnson for providing the K5-Cre mice. This work was supported by the Howard Hughes Medical Institute and grants from the US National Institutes of Health (R.R.R.).

Author information

C.T.L. co-designed and conducted all of the experiments and co-wrote the manuscript. P.A.C. provided unpublished mouse strains and guided experimental design. R.R.R. supervised the project, designed experimental protocols and was responsible for writing the manuscript.

Correspondence to Randall R Reed.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Rare incidences of LacZ+ non-HBC cells/clusters under normal condition. (PDF 665 kb)

Supplementary Fig. 2

Labeled HBCs express ICAM. (PDF 240 kb)

Supplementary Fig. 3

Proliferating basal cells. (PDF 395 kb)

Supplementary Fig. 4

Keratin 5 expression during postnatal OE development. (PDF 574 kb)

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Leung, C., Coulombe, P. & Reed, R. Contribution of olfactory neural stem cells to tissue maintenance and regeneration. Nat Neurosci 10, 720–726 (2007). https://doi.org/10.1038/nn1882

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