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Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic.

ABSTRACT: The purpose of this study was to ascertain the relative contribution of neural stem/progenitor cells (NSPCs) of the subventricular zone (SVZ) to lineages that repopulate the injured striatum following focal ischemia. We utilized a tamoxifen-inducible Cre/loxP system under control of the nestin promoter, which provides permanent YFP labeling of multipotent nestin(+) SVZ-NSPCs prior to ischemic injury and continued YFP expression in all subsequent progeny following stroke. YFP reporter expression was induced in adult male nestin-CreER(T2):R26R-YFP mice by tamoxifen administration (180 mg kg(-1), daily for 5 days). Fourteen days later, mice were subjected to 60-min transient middle cerebral artery occlusion (MCAO) and sacrificed at 2 days, 2 weeks, or 6 weeks post-MCAO for phenotypic fate mapping of YFP(+) cells using lineage-specific markers. Migration of YFP(+) cells from SVZ into the injured striatal parenchyma was apparent at 2 and 6 weeks, but not 2 days, post-MCAO. At 2 weeks post-MCAO, the average percent distribution of YFP(+) cells within the injured striatal parenchyma was as follows: 10% Dcx(+) neuroblasts, 15-20% oligodendrocyte progenitors, 59% GFAP(+) astrocytes, and only rare NeuN(+) postmitotic neurons. A similar phenotypic distribution was observed at 6 weeks, except for an increased average percentage of YFP(+) cells that expressed Dcx(+) (20%) or NeuN (5%). YFP(+) cells did not express endothelial markers, but displayed unique anatomical relationships with striatal vasculature. These results indicate that nestin(+) NSPCs within the SVZ mount a multilineage response to stroke that includes a gliogenic component more predominant than previously appreciated.

SUBMITTER: Li L

PROVIDER: S-EPMC2919586 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic.

Li Lu L Harms Kate M KM Ventura P Britten PB Lagace Diane C DC Eisch Amelia J AJ Cunningham Lee Anna LA

Glia 20101001 13

The purpose of this study was to ascertain the relative contribution of neural stem/progenitor cells (NSPCs) of the subventricular zone (SVZ) to lineages that repopulate the injured striatum following focal ischemia. We utilized a tamoxifen-inducible Cre/loxP system under control of the nestin promoter, which provides permanent YFP labeling of multipotent nestin(+) SVZ-NSPCs prior to ischemic injury and continued YFP expression in all subsequent progeny following stroke. YFP reporter expression ...[more]

PMID: 20578055

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Project description:The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator D-Penicillamine (D-Pen). A neurosphere model derived from adult mouse SVZ tissues was established and characterized for its functionality with regards to neural stem/progenitor cells (NSPCs). Applying D-Pen in cultured neurospheres significantly reduced intracellular Cu levels and reversed the Cu-induced suppression of NSPC's differentiation and migration. An in vivo intracerebroventricular (ICV) infusion model was subsequently established to infuse D-Pen directly into the lateral ventricle. Metal analyses revealed a selective reduction of Cu in SVZ by 13.1% (p = 0.19) and 21.4% (p < 0.05) following D-Pen infusions at low (0.075 μg/h) and high (0.75 μg/h) doses for 28 days, respectively, compared to saline-infused controls. Immunohistochemical studies revealed that the 7-day, low-dose D-Pen infusion significantly increased Ki67(+)/Nestin(+) cell counts in SVZ by 28% (p < 0.05). Quantification of BrdU(+)/doublecortin (DCX)(+) newborn neuroblasts in the rostral migration stream (RMS) and olfactory bulb (OB) further revealed that the short-term, low-dose D-Pen infusion, as compared with saline-infused controls, resulted in more newborn neuroblasts in OB, while the high-dose D-Pen infusion showed fewer newborn neuroblasts in OB but with more arrested in the RMS. Long-term (28-day) infusion revealed similar outcomes. The qPCR data from neurosphere experiments revealed altered expressions of mRNAs encoding key proteins known to regulate SVZ adult neurogenesis, including, but not limited to, Shh, Dlx2, and Slit1, in response to the changed Cu level in neurospheres. Further immunohistochemical data indicated that Cu chelation also altered the expression of high-affinity copper uptake protein 1 (CTR1) and metallothionein-3 (MT3) in the SVZ as well as CTR1 in the choroid plexus, a tissue regulating brain Cu homeostasis. Taken together, this study provides first-hand evidence that a high Cu level in SVZ appears likely to maintain the stability of adult neurogenesis in this neurogenic zone.

Dataset Information

Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic.

Publications

Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic.

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