title: Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability.
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 (14day) 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.
authors.affiliation: Farber Institute of Neurosciences, Department of Neuroscience, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Ruihe
authors.initials: R
authors.lastname: Lin
authors.affiliation: Farber Institute of Neurosciences, Department of Neuroscience, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jingli
authors.initials: J
authors.lastname: Cai
authors.affiliation: Farber Institute of Neurosciences, Department of Neuroscience, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Cody
authors.initials: C
authors.lastname: Nathan
authors.affiliation: Farber Institute of Neurosciences, Department of Neuroscience, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Wei
authors.affiliation: Farber Institute of Neurosciences, Department of Neuroscience, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schleidt
authors.affiliation: Department of Neurological Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenwasser
authors.affiliation: Farber Institute of Neurosciences, Department of Neuroscience, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: Lorraine.iacovitti@jefferson.edu.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Iacovitti
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation / Q000502:physiology; D002552:Cerebral Ventricles; D004195:Disease Models, Animal; D018450:Disease Progression; D000089662:Doublecortin Protein; D019793:Fluorescein; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009836:Oligodendroglia / Q000473:pathology / Q000502:physiology; D017207:Rats, Sprague-Dawley; D055153:Stem Cell Niche / Q000502:physiology*; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D019793:Fluorescein
keywords: Blood brain barrier; CVO; Neural stem cell; Neurogenesis; Stroke