- Stem cells
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.
Copyright © 2010 S. Karger AG, Basel
- Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O: Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002;8:963–970.
- Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM: Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 2002;52:802–813.
- Yang Z, Levison SW: Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone. Neuroscience 2006;139:555–564.
- Plane JM, Liu R, Wang TW, Silverstein FS, Parent JM: Neonatal hypoxic-ischemic injury increases forebrain subventricular zone neurogenesis in the mouse. Neurobiol Dis 2004;16:585–595.
- Ong J, Plane JM, Parent JM, Silverstein FS: Hypoxic-ischemic injury stimulates subventricular zone proliferation and neurogenesis in the neonatal rat. Pediatr Res 2005;58:600–606.
- Ackman JB, Siddiqi F, Walikonis RS, LoTurco JJ: Fusion of microglia with pyramidal neurons after retroviral infection. J Neurosci 2006;26:11413–11422.
- Kuhn HG, Cooper-Kuhn CM: Bromodeoxyuridine and the detection of neurogenesis. Curr Pharm Biotechnol 2007;8:127–131.
- Taupin P: BrdU immunohistochemistry for studying adult neurogenesis: Paradigms, pitfalls, limitations, and validation. Brain Res Rev 2007;53:198–214.
- Sergent-Tanguy S, Michel DC, Neveu I, Naveilhan P: Long-lasting coexpression of nestin and glial fibrillary acidic protein in primary cultures of astroglial cells with a major participation of nestin(+)/GFAP(–) cells in cell proliferation. J Neurosci Res 2006;83:1515–1524.
- Lois C, Alvarez-Buylla A: Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 1993;90:2074–2077.
- Doetsch F, Alvarez-Buylla A: Network of tangential pathways for neuronal migration in adult mammalian brain. Proc Natl Acad Sci USA 1996;93:14895–14900.
- Levison SW, Goldman JE: Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Neuron 1993;10:201–212.
- Suzuki SO, Goldman JE: Multiple cell populations in the early postnatal subventricular zone take distinct migratory pathways: a dynamic study of glial and neuronal progenitor migration. J Neurosci 2003;23:4240–4250.
- Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999;97:703–716.
- Merkle FT, Tramontin AD, Garcia-Verdugo JM, Alvarez-Buylla A: Radial glia give rise to adult neural stem cells in the subventricular zone. Proc Natl Acad Sci USA 2004;101:17528–17532.
- Mirzadeh Z, Merkle FT, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A: Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 2008;3:265–278.
- Merkle FT, Alvarez-Buylla A: Neural stem cells in mammalian development. Curr Opin Cell Biol 2006;18:704–709.
- Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D: Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 2002;295:868–872.
- Geraerts M, Eggermont K, Hernandez-Acosta P, Garcia-Verdugo JM, Baekelandt V, Debyser Z: Lentiviral vectors mediate efficient and stable gene transfer in adult neural stem cells in vivo. Hum Gene Ther 2006;17:635–650.
- Carlen M, Meletis K, Goritz C, Darsalia V, Evergren E, Tanigaki K, Amendola M, Barnabe-Heider F, Yeung MS, Naldini L, Honjo T, Kokaia Z, Shupliakov O, Cassidy RM, Lindvall O, Frisen J: Forebrain ependymal cells are notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci 2009;12:259–267.
- Derugin N, Ferriero DM, Vexler ZS: Neonatal reversible focal cerebral ischemia: a new model. Neurosci Res 1998;32:349–353.
- Gonzalez FF, McQuillen P, Mu D, Chang Y, Wendland M, Vexler Z, Ferriero DM: Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Dev Neurosci 2007;29:321–330.
- Yang Z, Covey MV, Bitel CL, Ni L, Jonakait GM, Levison SW: Sustained neocortical neurogenesis after neonatal hypoxic/ischemic injury. Ann Neurol 2007;61:199–208.
- Zerlin M, Levison SW, Goldman JE: Early patterns of migration, morphogenesis, and intermediate filament expression of subventricular zone cells in the postnatal rat forebrain. J Neurosci 1995;15:7238–7249.
- Chang YS, Mu D, Wendland M, Sheldon RA, Vexler ZS, McQuillen PS, Ferriero DM: Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res 2005;58:106–111.
- Burns KA, Ayoub AE, Breunig JJ, Adhami F, Weng WL, Colbert MC, Rakic P, Kuan CY: Nestin-creer mice reveal DNA synthesis by nonapoptotic neurons following cerebral ischemia hypoxia. Cereb Cortex 2007;17:2585–2592.
- Levison SW, Rothstein RP, Romanko MJ, Snyder MJ, Meyers RL, Vannucci SJ: Hypoxia/ischemia depletes the rat perinatal subventricular zone of oligodendrocyte progenitors and neural stem cells. Dev Neurosci 2001;23:234–247.
- Romanko MJ, Zhu C, Bahr BA, Blomgren K, Levison SW: Death effector activation in the subventricular zone subsequent to perinatal hypoxia/ischemia. J Neurochem 2007;103:1121–1131.
- Iwai M, Ikeda T, Hayashi T, Sato K, Nagata T, Nagano I, Shoji M, Ikenoue T, Abe K: Temporal profile of neural stem cell proliferation in the subventricular zone after ischemia/hypoxia in the neonatal rat brain. Neurol Res 2006;28:461–468.
- Kadam SD, Mulholland JD, McDonald JW, Comi AM: Poststroke subgranular and rostral subventricular zone proliferation in a mouse model of neonatal stroke. J Neurosci Res 2009;87:2653–2666.
- Cooper-Kuhn CM, Kuhn HG: Is it all DNA repair? Methodological considerations for detecting neurogenesis in the adult brain. Brain Res Dev Brain Res 2002;134:13–21.
- Kuan CY, Schloemer AJ, Lu A, Burns KA, Weng WL, Williams MT, Strauss KI, Vorhees CV, Flavell RA, Davis RJ, Sharp FR, Rakic P: Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. J Neurosci 2004;24:10763–10772.
- Iwai M, Cao G, Yin W, Stetler RA, Liu J, Chen J: Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats. Stroke 2007;38:2795–2803.
- Chen ZY, Asavaritikrai P, Prchal JT, Noguchi CT: Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 2007;282:25875–25883.
- Seri B, Herrera DG, Gritti A, Ferron S, Collado L, Vescovi A, Garcia-Verdugo JM, Alvarez-Buylla A: Composition and organization of the SCZ: a large germinal layer containing neural stem cells in the adult mammalian brain. Cereb Cortex 2006;16 (suppl 1):I103–I111.
- Laskowski A, Howell OW, Sosunov AA, McKhann G, Gray WP: NPY mediates basal and seizure-induced proliferation in the subcallosal zone. Neuroreport 2007;18:1005–1008.
- Nakagomi T, Taguchi A, Fujimori Y, Saino O, Nakano-Doi A, Kubo S, Gotoh A, Soma T, Yoshikawa H, Nishizaki T, Nakagomi N, Stern DM, Matsuyama T: Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice. Eur J Neurosci 2009;29:1842–1852.
- Burns KA, Murphy B, Danzer SC, Kuan CY: Developmental and post-injury cortical gliogenesis: a genetic fate-mapping study with nestin-creER mice. Glia 2009;57:1115–1129.
- Biran V, Joly LM, Heron A, Vernet A, Vega C, Mariani J, Renolleau S, Charriaut-Marlangue C: Glial activation in white matter following ischemia in the neonatal P7 rat brain. Exp Neurol 2006;199:103–112.
- Segovia KN, McClure M, Moravec M, Luo NL, Wan Y, Gong X, Riddle A, Craig A, Struve J, Sherman LS, Back SA: Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury. Ann Neurol 2008;63:520–530.
- Sellers DL, Maris DO, Horner PJ: Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci 2009;29:6722–6733.
- Guo F, Ma J, McCauley E, Bannerman P, Pleasure D: Early postnatal proteolipid promoter-expressing progenitors produce multilineage cells in vivo. J Neurosci 2009;29:7256–7270.
- Rothstein RP, Levison SW: Gray matter oligodendrocyte progenitors and neurons die caspase-3-mediated deaths subsequent to mild perinatal hypoxic/ischemic insults. Dev Neurosci 2005;27:149–159.
Prof. Donna M. Ferriero, MD
University of California, San Francisco
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Received: July 27, 2009
Accepted after revision: January 21, 2010
Published online: May 4, 2010
Number of Print Pages : 13
Number of Figures : 5, Number of Tables : 0, Number of References : 43
Additional supplementary material is available online - Number of Parts : 1
Vol. 32, No. 2, Year 2010 (Cover Date: July 2010)
Journal Editor: Levison S.W. (Newark, N.J.)
ISSN: 0378-5866 (Print), eISSN: 1421-9859 (Online)
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