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Primitive Neural Stem Cells: It’s Quiescent at the Top!

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Review of “Quiescent Oct4+ neural stem cells (NSCs) repopulate ablated GFAP+ NSCs in the adult mouse brain” from STEM CELLS by Stuart P. Atkinson

Mammalian neural stem cells (NSCs) exist as a heterogeneous population of cells, although most so-called “definitive” (d)NSCs express the glial fibrillary acidic protein (GFAP) [1]. However, studies from the laboratory of Rachel L. Reeve (University of Toronto, Canada) identified a population of GFAP-negative Oct4-positive primitive (p)NSCs [2], which arise very early in embryo development [3] and persist through to adulthood.

In their new STEM CELLS study, Reeve et al. now indicate that quiescent pNSCs lie at the zenith of the neural cell lineage, upstream of dNSCs, and enter a proliferative state to repopulate lost dNSCs and their downstream neural lineage [4].

Initial label retention experiments suggested that while mouse dNSCs divided every 2 to 4 weeks, pNSCs residing within the forebrain subependymal zone only divided once every 3 to 5 months, suggesting that pNSCs preferentially reside in a quiescent state. Furthermore, the artificially-induced loss of dNSCs prompted pNSCs to leave this quiescent state and to begin proliferating. These findings suggested that pNSCs may lie upstream of the dNSC lineage and may act to recover any loss in numbers to the dNSC population. 

To confirm these findings, the authors modeled pNSC loss of function via the conditional knockout of Oct4-positive cells (and hence pNSCs) after embryonic day 7.4. The knockout of Oct4 inhibited pNSC function, as evidenced by a lack of neurosphere formation. Additionally, while wild type animals could repopulate their dNSC population following an artificially induced loss of all GFAP+ dNSCs, Oct4 knockout animals with no functioning pNSCs lacked this ability.

Overall, the authors propose that quiescent pNSCs lie upstream of dNSCs, and proliferate in response to the loss of dNSCs. Could cells such as these represent a highly regenerative cell type with potential for the treatment of various neural diseases and disorders? 

Keep tuned to the Stem Cells Portal to find out more!

References

  1. Doetsch F, Caille I, Lim DA, et al. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999;97:703-716.
  2. Sachewsky N, Leeder R, Xu W, et al. Primitive neural stem cells in the adult mammalian brain give rise to GFAP-expressing neural stem cells. Stem Cell Reports 2014;2:810-824.
  3. Hitoshi S, Seaberg RM, Koscik C, et al. Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling. Genes Dev 2004;18:1806-1811.
  4. Reeve RL, Yammine SZ, Morshead CM, et al. Quiescent Oct4+ Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein+ NSCs in the Adult Mouse Brain. Stem Cells 2017;35:2071-2082.