Activated Neural Stem Cells Contribute to Stroke-Induced Neurogenesis and Neuroblast Migration toward the Infarct Boundary in Adult Rats

Stroke increases neurogenesis. The authors investigated whether neural stem cells or progenitor cells in the adult subventricular zone (SVZ) of rats contribute to stroke-induced increase in neurogenesis. After induction of stroke in rats, the numbers of cells immunoreactive to doublecortin, a marker for immature neurons, increased in the ipsilateral SVZ and striatum. Infusion of an antimitotic agent (cytosine-β-D-arabiofuranoside, Ara-C) onto the ipsilateral cortex eliminated more than 98% of actively proliferating cells in the SVZ and doublecortin-positive cells in the ipsilateral striatum. However, doublecortin-positive cells rapidly replenished after antimitotic agent depletion of actively proliferating cells. Depleting the numbers of actively proliferating cells in vivo had no effect on the numbers of neurospheres formed in vitro, yet the numbers of neurospheres derived from stroke rats significantly (P < 0.05) increased. Neurospheres derived from stroke rats self-renewed and differentiated into neurons and glia. In addition, doublecortin-positive cells generated in the SVZ migrated in a chainlike structure toward ischemic striatum. These findings indicate that in the adult stroke brain, increases in recruitment of neural stem cells contribute to stroke-induced neurogenesis, and that newly generated neurons migrate from the SVZ to the ischemic striatum.

[1]  Koji Abe,et al.  Temporal Profile of Stem Cell Division, Migration, and Differentiation from Subventricular Zone to Olfactory Bulb after Transient Forebrain Ischemia in Gerbils , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[3]  Jack M Parent,et al.  Rat forebrain neurogenesis and striatal neuron replacement after focal stroke , 2002, Annals of neurology.

[4]  J. García-Verdugo,et al.  Architecture and cell types of the adult subventricular zone: in search of the stem cells. , 1998, Journal of neurobiology.

[5]  D. van der Kooy,et al.  Transforming Growth Factor-α Null and Senescent Mice Show Decreased Neural Progenitor Cell Proliferation in the Forebrain Subependyma , 1997, The Journal of Neuroscience.

[6]  B. McEwen,et al.  Doublecortin expression in the adult rat telencephalon , 2001, The European journal of neuroscience.

[7]  Yingwang,et al.  Sildenafil (Viagra) Induces Neurogenesis and Promotes Functional Recovery After Stroke in Rats , 2002 .

[8]  J. García-Verdugo,et al.  Cellular Composition and Three-Dimensional Organization of the Subventricular Germinal Zone in the Adult Mammalian Brain , 1997, The Journal of Neuroscience.

[9]  S. Finklestein,et al.  Increased expression of basic fibroblast growth factor (bFGF) following focal cerebral infarction in the rat. , 1996, Brain research. Molecular brain research.

[10]  D. van der Kooy,et al.  Adult Rodent Neurogenic Regions: The Ventricular Subependyma Contains Neural Stem Cells, But the Dentate Gyrus Contains Restricted Progenitors , 2002, The Journal of Neuroscience.

[11]  S. Mcconnell,et al.  Doublecortin Is a Developmentally Regulated, Microtubule-Associated Protein Expressed in Migrating and Differentiating Neurons , 1999, Neuron.

[12]  M. Moskowitz,et al.  FGF-2 regulation of neurogenesis in adult hippocampus after brain injury , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  E. Parati,et al.  Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[15]  Brent A. Reynolds,et al.  Neural stem cells in the adult mammalian forebrain: A relatively quiescent subpopulation of subependymal cells , 1994, Neuron.

[16]  S. Higashiyama,et al.  Heparin-binding epidermal growth factor-like growth factor mRNA expression in neonatal rat brain with hypoxic/ischemic injury , 1999, Brain Research.

[17]  Michael Chopp,et al.  A rat model of focal embolic cerebral ischemia , 1997, Brain Research.

[18]  C. Justicia,et al.  Epidermal growth factor receptor in proliferating reactive glia following transient focal ischemia in the rat brain , 1998, Glia.

[19]  Lin Xie,et al.  Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum , 2003, Molecular and Cellular Neuroscience.

[20]  R. Galli,et al.  Neural Stem Cells: An Overview , 2003, Circulation research.

[21]  D. van der Kooy,et al.  In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  Hirofumi Nakatomi,et al.  Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors , 2002, Cell.

[23]  M Chopp,et al.  Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia , 2001, Neuroscience.

[24]  P. Pullman,et al.  I was a rat , 2002 .

[25]  C. Walsh,et al.  Protein–Protein interactions, cytoskeletal regulation and neuronal migration , 2001, Nature Reviews Neuroscience.

[26]  J. García-Verdugo,et al.  Regeneration of a germinal layer in the adult mammalian brain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Luskin.  Neuroblasts of the postnatal mammalian forebrain: their phenotype and fate. , 1998, Journal of neurobiology.

[28]  D. van der Kooy,et al.  In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. , 1998, Development.

[29]  D. van der Kooy,et al.  Adult Mammalian Forebrain Ependymal and Subependymal Cells Demonstrate Proliferative Potential, but only Subependymal Cells Have Neural Stem Cell Characteristics , 1999, The Journal of Neuroscience.

[30]  O. Lindvall,et al.  Neuronal replacement from endogenous precursors in the adult brain after stroke , 2002, Nature Medicine.

[31]  David A. Greenberg,et al.  Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat , 2001, Proceedings of the National Academy of Sciences of the United States of America.