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Understanding Neurogenesis within the Olfactory Stem Cell Niche

Review of “Chemokine signaling is required for homeostatic and injury‐induced neurogenesis in the olfactory epithelium” from STEM CELLS by Stuart P. Atkinson

The persistence of self‐renewing stem cells in the mammalian olfactory epithelium supports lifelong neurogenesis and neuroregeneration [1, 2] and complete regeneration after the loss of mature cells [3]. While horizontal basal cells (HBCs) represent quiescent reserve stem cells [4], the globose basal cells (GBCs) actively proliferate to permit continuous olfactory neurogenesis [5, 6]. Therefore, there has been significant interest in the olfactory epithelium as a model for adult neurogenesis and a source of therapeutically relevant and accessible autologous neural stem cells.

In a recent STEM CELLS study [7], researchers led by Eva M. Neuhaus (Jena University Hospital, Jena, Germany) describe their exploration of the microenvironmental factors balancing differentiation and self‐renewal of olfactory epithelial stem cells, which focused on neurogenic signaling through the chemokine CXCL12 and its cognate receptor CXCR4 [8]. Overall, their results deepen our understanding of olfactory stem cell niche signaling under steady-state and regenerative conditions and suggest a means to improve autologous olfactory stem cell transplantation approaches.

Initial colocalization analysis by Senf et al. revealed that only proliferative GBCs and their neuronal progenitor progeny (and not HBCs) expressed elevated levels of CXCR4 and only these cells gave rise to neuronal lineage cells in the olfactory epithelium under steady-state conditions. Of note, the levels of CXRX4 expression were much higher in GBCs compared to hippocampal stem cells, suggesting that CXCR4 may support the high rates of neurogenesis in the olfactory epithelium.

During epithelial regeneration following methimazole‐induced injury, activated HBCs transitioned into GBCs, and a considerable increase in the expression of both CXCR4 and CXCL12 accompanied the induced proliferation and expansion of GBCs; however, the perturbation of CXCR4 signaling by the overexpression of CXCL12 (which mimics knockout of Cxcr4) prompted a downregulation of CXCR4 levels, a reduction in proliferation, and the neuronal differentiation of GBCs.

Overall, the authors highlight the critical role of microenvironmental CXCR4 signaling in neurogenesis within the postnatal olfactory epithelium to support the maintenance of normal cellular turnover and regeneration/restoration following injury. Given the existence of pharmacological tools that impact CXCR4/CXCL12 signaling, the authors believe that their findings may help to develop in vitro culture strategies of olfactory epithelium stem cells towards their application in transplant therapies.

For more on the importance of CXCR4-based signaling and further explorations of stem cells of the olfactory epithelium, stay tuned to the Stem Cells Portal!


References

  1. Mackay-Sim A and Kittel P, Cell dynamics in the adult mouse olfactory epithelium: a quantitative autoradiographic study. The Journal of Neuroscience 1991;11:979.
  2. Graziadei PPC and Graziadei GAM, Neurogenesis and neuron regeneration in the olfactory system of mammals. I. Morphological aspects of differentiation and structural organization of the olfactory sensory neurons. Journal of Neurocytology 1979;8:1-18.
  3. Schwob JE, Youngentob SL, and Mezza RC, Reconstitution of the rat olfactory epithelium after methyl bromide-induced lesion. Journal of Comparative Neurology 1995;359:15-37.
  4. Herrick DB, Guo Z, Jang W, et al., Canonical Notch Signaling Directs the Fate of Differentiating Neurocompetent Progenitors in the Mammalian Olfactory Epithelium. The Journal of Neuroscience 2018;38:5022.
  5. Schwob JE, Jang W, Holbrook EH, et al., Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license. Journal of Comparative Neurology 2017;525:1034-1054.
  6. Schwob JE, Huard JMT, Luskin MB, et al., Retroviral lineage studies of the rat olfactory epithelium. Chemical Senses 1994;19:671-682.
  7. Senf K, Karius J, Stumm R, et al., Chemokine signaling is required for homeostatic and injury-induced neurogenesis in the olfactory epithelium. STEM CELLS 2021;39:617-635.
  8. Li M and Ransohoff RM, Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology. Progress in Neurobiology 2008;84:116-131.