Abstract
SummaryAdult forebrain definitive neural stem cells (NSCs) comprise a subpopulation of GFAP-expressing subependymal cells that arise from embryonic fibroblast growth factor (FGF)-dependent NSCs that are first isolated from the developing brain at E8.5. Embryonic FGF-dependent NSCs are derived from leukemia inhibitory factor (LIF)-responsive, Oct4-expressing primitive NSCs (pNSCs) that are first isolated at E5.5. We report the presence of a rare population of pNCSs in the periventricular region of the adult forebrain. Adult-derived pNSCs (AdpNSCs) are GFAP−, LIF-responsive stem cells that display pNSC properties, including Oct4 expression and the ability to integrate into the inner cell mass of blastocysts. AdpNSCs generate self-renewing, multipotent colonies that give rise to definitive GFAP+ NSCs in vitro and repopulate the subependyma after the ablation of GFAP+ NSCs in vivo. These data support the hypothesis that a rare population of pNSCs is present in the adult brain and is upstream of the GFAP+ NSCs.
Highlights
Neural stem cells (NSCs) in the adult brain reside in the periventricular region, where they generate progeny that migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB) and become interneurons (Chojnacki et al, 2009; Garcia et al, 2004; Mirzadeh et al, 2008; Morshead et al, 1994)
Adult forebrain definitive neural stem cells (NSCs) comprise a subpopulation of GFAP-expressing subependymal cells that arise from embryonic fibroblast growth factor (FGF)-dependent NSCs that are first isolated from the developing brain at E8.5
Embryonic FGFdependent NSCs are derived from leukemia inhibitory factor (LIF)-responsive, Oct4-expressing primitive NSCs that are first isolated at E5.5
Summary
Neural stem cells (NSCs) in the adult brain reside in the periventricular region, where they generate progeny that migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB) and become interneurons (Chojnacki et al, 2009; Garcia et al, 2004; Mirzadeh et al, 2008; Morshead et al, 1994). Numerous studies suggest that adult forebrain NSCs comprise a subpopulation of GFAP-expressing (GFAP+) cells within the subependyma (SE) lining the lateral ventricles (termed type B cells) (Capela and Temple, 2002; Chiasson et al, 1999; Doetsch et al, 1999a; Morshead et al, 2003). The GFAP+ NSCs generate clonally derived, multipotent, self-renewing colonies (termed neurospheres) in the presence of growth factors (epidermal growth factor [EGF] and fibroblast growth factor 2 [FGF2]) in vitro (Doetsch et al, 1999a; Imura et al, 2003; Morshead et al, 2003). The GFAP+ adult NSCs are derived from embryonic definitive NSCs and the two types of cells share similar properties, including FGF2 and EGF responsiveness, self-renewal, and multipotentiality (Hitoshi et al, 2004; Tropepe et al, 2001). Leukemia inhibitory factor (LIF)-dependent primitive NSCs (pNSCs) are present at E5.5 and give rise to FGF2responsive NSCs beginning at E8.5, which go on to generate GFAP+, neurosphere-forming, definitive NSCs in the adult brain
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