Elsevier

Neurobiology of Disease

Volume 74, February 2015, Pages 229-239
Neurobiology of Disease

Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability

https://doi.org/10.1016/j.nbd.2014.11.016Get rights and content
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Highlights

  • Stem cell niches exist along the entire ventricular system in the adult rat brain.

  • Stroke induces widespread neurogenesis and gliogenesis in all adult brain niches.

  • Niches access systemic injury cues via a permeable BBB, made leakier by stroke.

  • All stem cell niches are induced following bFGF infusion into the CSF.

Abstract

Previous studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain (Doetsch et al., 1999a; Doetsch, 2003a). Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14 day) rise in the proliferation (BrdU +) of nestin + Sox2 + GFAP + NSCs capable of differentiating into Olig2 + glial progenitors, GFAP + nestin-astrocyte progenitors and Dcx + neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a blood–brain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair.

Keywords

Stroke
CVO
Neurogenesis
Neural stem cell
Blood brain barrier

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