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New Study Describes Neural Stem Cells in the Mouse Olfactory Bulb

Review of "Neural stem cells in the adult olfactory bulb core generate mature neurons in vivo" from STEM CELLS by Stuart P. Atkinson

Although the subventricular zone of the postnatal lateral ventricle represents the primary source of olfactory bulb interneurons, a range of studies has claimed that local neural stem cells (NSCs) exist in the adult rodent and human olfactory bulb. These studies have been supported by research that described the generation of neurons and glia from human olfactory bulb cells during in vitro culture [1-6] (See the STEM CELLS article here!).

Given these findings, researchers led by Carlos Vicario (Instituto Cajal-Consejo Superior de Investigaciones Científicas [CSIC], Madrid, Spain) sought to define the precise in vivo location and full neurogenic potential of olfactory bulb NSCs by retroviral labeling to characterize the dividing cells and analyzing cell marker expression, morphology, and connectivity. As detailed in their recent STEM CELLS article, Defteralı et al. now provide evidence that olfactory bulb NSCs give rise to calretinin-expressing interneurons that become incorporated into the olfactory bulb circuitry [7].

The authors began by injecting fluorescently-labeled retroviruses into the olfactory bulb core of adult mice – this approach labels any dividing cells and tracks the differentiation/maturation of any subsequently generated neurons. While fluorescently-labeled cells also expressed markers of adult NSCs soon after injection (up to three days), the abundance of fluorescent cells co-expressing doublecortin (DCX - a marker of neuroblasts and immature neurons) steadily increased over seven days. Additionally, the presumed olfactory bulb NSCs also gave rise to NeuN-positive neurons that then began to express markers of olfactory bulb neuron subtypes; however, the authors noted that interneurons expressing calretinin (a calcium-binding protein) represented the most abundant cell type generated.

Encouragingly, the authors also found evidence that olfactory bulb NSC-derived neurons expressed presynaptic proteins and the transcription factor pCREB and established asymmetric and symmetric synaptic contacts with existing neurons and the olfactory nerve. Overall, these findings provided robust evidence that olfactory bulb NSC-derived cells became incorporated into the olfactory bulb circuitry.

Of particular note, tracking NSCs and neurons from the subventricular zone using the same labeling strategy revealed the presence of slowly dividing label-retaining cells that may represent resident NSCs; however, the post-mitotic nature of the vast majority of cells that eventually reached the olfactory bulb core strongly suggested that proliferating cells of the olfactory bulb do not derive from the subventricular zone.

Overall, this exciting in vivo study strongly suggests that NSCs within the mouse olfactory bulb contribute to the generation of neurons that incorporate themselves into the olfactory bulb circuitry. The authors note that future studies may include the determination of whether the presumed human olfactory bulb-derived NSCs react to pathological or physiological stimulation and generate functional interneurons to extend their research.

For more on the characteristics and activity of olfactory bulb neural stem cells, stay tuned to the Stem Cells Portal!

References

  1. Marei HES, Farag A, Althani A, et al., Human Olfactory Bulb Neural Stem Cells expressing hNGF Restore Cognitive Deficit in Alzheimer's Disease Rat Model. Journal of Cellular Physiology 2015;230:116-130.
  2. Marei HE, Shouman Z, Althani A, et al., Differentiation of human olfactory bulb-derived neural stem cells toward oligodendrocyte. Journal of Cellular Physiology 2018;233:1321-1329.
  3. Pagano SF, Impagnatiello F, Girelli M, et al., Isolation and Characterization of Neural Stem Cells from the Adult Human Olfactory Bulb. STEM CELLS 2000;18:295-300.
  4. Marei HES, Ahmed A-E, Michetti F, et al., Gene Expression Profile of Adult Human Olfactory Bulb and Embryonic Neural Stem Cell Suggests Distinct Signaling Pathways and Epigenetic Control. PLOS ONE 2012;7:e33542.
  5. Marei HES and Ahmed A-E, Transcription factors expressed in embryonic and adult olfactory bulb neural stem cells reveal distinct proliferation, differentiation and epigenetic control. Genomics 2013;101:12-19.
  6. Alizadeh R, Hassanzadeh G, Joghataei MT, et al., In vitro differentiation of neural stem cells derived from human olfactory bulb into dopaminergic-like neurons. European Journal of Neuroscience 2017;45:773-784.
  7. Defteralı Ç, Moreno-Estellés M, Crespo C, et al., Neural stem cells in the adult olfactory bulb core generate mature neurons in vivo. STEM CELLS 2021;39:1253-1269.