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Altered Fate of Subventricular Zone Progenitor Cells and Reduced Neurogenesis following Neonatal StrokeSpadafora R.a · Gonzalez F.F.a, b · Derugin N.c · Wendland M.d · Ferriero D.a, b · McQuillen P.a, b
Departments of aNeurology, bPediatrics, cNeurosurgery, and dRadiology, University of California, San Francisco, Calif., USA Corresponding Author
Prof. Donna M. Ferriero, MD
University of California, San Francisco
521 Parnassus Avenue, Rm C215
San Francisco, CA 94143-0663 (USA)
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Objective: To investigate the effects of neonatal stroke on progenitor cells lining the lateral ventricles. Methods: Intraventricular injection of replication-incompetent green fluorescent protein (GFP)-expressing lentivirus was performed in postnatal day 1 (P1) rats to specifically label radial glia/type B neural stem cells and ependymal cells of the lateral ventricle. A subset of animals was exposed to transient middle cerebral artery occlusion (MCAO) at P7, with mild or moderate injury confirmed by diffusion-weighted MRI and histology. Newborn cells were identified by GFP expression, location and expression of cell type-specific markers in the striatum, cortex and olfactory bulb using confocal microscopy and systematic random sampling. Results: Three weeks lentiviral GFP transduction of cells in the lateral ventricle, abundant GFP-expressing neurons and glia were identified in the rostral migratory stream, olfactory bulb and striatum as expected from labeling the subventricular zone (SVZ) type B neural stem cell lineage. Two weeks following mild or severe focal stroke at P7, no GFP-expressing neurons were detected in striatum or cortex although some single-labeled doublecortin+ immature neurons were detected in the penumbra. The densities of GFP+/ glial fibrillary acidic protein (GFAP)+ astrocytes and GFP+/O4+ oligodendrocytes were reduced in the striatum following MCAO (4.8 ± 1.02 vs. 2.5 ± 0.4 cells/high-power field, HPF; p = 0.005; 2.8± 1 vs. 0.5 ± 0.2 cells/HPF, p = 0.008). Furthermore, there was a reduction of GFP+ cells in the olfactory bulb following MCAO (58.8 ± 14.9 vs. 19.6 ± 5.4 cells/HPF, p = 0.025). Finally, there was an increased percentage of GFP+/GFAP+ cells (70 vs. 50%), with a decreased proportion of GFP+/O4+ cells (14 vs. 30%) in injured animals. Conclusion: Neurogenesis originating from cells of the lateral ventricle, including SVZ type B cells, is significantly reduced following neonatal stroke. Furthermore, neonatal stroke disrupts gliogenesis in the striatum, decreasing overall numbers of new glia and shifting the population towards astrocytes.
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