Quiescent Oct4+ Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein+ NSCs in the Adult Mouse Brain

Author:

Reeve Rachel L.1ORCID,Yammine Samantha Z.2,Morshead Cindi M.3,van der Kooy Derek12

Affiliation:

1. a Institute of Medical Sciences, University of Toronto, Toronto, Canada

2. b Department of Molecular Genetics, University of Toronto, Toronto, Canada

3. c Department of Surgery, University of Toronto, Toronto, Canada

Abstract

Abstract Adult primitive neural stem cells (pNSCs) are a rare population of glial fibrillary acidic protein (GFAP)– Oct4+ cells in the mouse forebrain subependymal zone bordering the lateral ventricles that give rise to clonal neurospheres in leukemia inhibitory factor in vitro. pNSC neurospheres can be passaged to self-renew or give rise to GFAP+ NSCs that form neurospheres in epidermal growth factor and fibroblast growth factor 2, which we collectively refer to as definitive NSCs (dNSCs). Label retention experiments using doxycycline-inducible histone-2B (H2B)–green fluorescent protein (GFP) mice and several chase periods of up to 1 year quantified the adult pNSC cell cycle time as 3–5 months. We hypothesized that while pNSCs are not very proliferative at baseline, they may exist as a reserve pool of NSCs in case of injury. To test this function of pNSCs, we obtained conditional Oct4 knockout mice, Oct4fl/fl;Sox1Cre (Oct4CKO), which do not yield adult pNSC-derived neurospheres. When we ablated the progeny of pNSCs, namely all GFAP+ dNSCs, in these Oct4CKO mice, we found that dNSCs did not recover as they do in wild-type mice, suggesting that pNSCs are necessary for dNSC repopulation. Returning to the H2B-GFP mice, we observed that the cytosine β-d-arabinofuranoside ablation of proliferating cells including dNSCs-induced quiescent pNSCs to proliferate and significantly dilute their H2B-GFP label. In conclusion, we demonstrate that pNSCs are the most quiescent stem cells in the adult brain reported to date and that their lineage position upstream of GFAP+ dNSCs allows them to repopulate a depleted neural lineage.

Funder

CIHR

CFREF

Canadian Stem Cell Network

Ontario Brain Institute

NeuroDevNet NCE

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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4. Primitive neural stem cells in the adult mammalian brain give rise to GFAP-expressing neural stem cells;Sachewsky;Stem Cell Rep,2014

5. Targeted activation of primitive neural stem cells in the mouse brain;Reeve;Eur J Neurosci.,2016

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