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

Abstract

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-beta-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.

Stroke Induces Gene Profile Changes Associated with Neurogenesis and Angiogenesis in Adult Subventricular Zone Progenitor Cells

“…The present study shows that stroke substantially upregulated Bmp 8, Gdf 2, Bmp type I receptors, and activin receptors in SVZ cells. Stroke promotes proliferation of SVZ cells and enhances SVZ cell differentiation into neurons (Zhang et al, 2001(Zhang et al, , 2004(Zhang et al, , 2005bParent et al, 2002). Upregulation of Bmps and their receptors in SVZ cells after stroke suggests that these signaling molecules could mediate stroke-induced neurogenesis in the adult SVZ.…”

“…Neural stem cells in the SVZ give rise to neuroblasts that travel the rostral migratory stream to the olfactory bulb, where they differentiate into granule and periglomerular neurons throughout adult life (Morshead et al, 1994;Garcia-Verdugo et al, 1998;Luskin, 1998). Stroke increases neurogenesis in the SVZ and newly generated neuroblasts migrate towards ischemic boundary regions (Arvidsson et al, 2002;Jin et al, 2001;Parent et al, 2002;Zhang et al, 2001Zhang et al, , 2004. However, genes that control proliferation, differentiation, and migration of neural progenitor cells in the adult SVZ have not been fully investigated.…”

Coupling of Angiogenesis and Neurogenesis in Cultured Endothelial Cells and Neural Progenitor Cells after Stroke

“…Immunofluorescent staining was performed as described previously (Wang et al, 2004b;Zhang et al, 2004). Briefly, cells were fixed in 4% (w/v) paraformaldehyde, and nonspecific binding was blocked by a block solution containing of 1% (w/v) bovine serum albumin and 0.3% Triton-100 (v/v) for 1 h at room temperature.…”

“…The number of TuJ-1-, GFAP-, or BrdU-positive cells and the total number of 4 0 ,6 0 -diamidino-2-phenylindole cells per field were counted and the percentage of each cell type per field was determined (Wang et al, 2004b;Zhang et al, 2004).…”

Reduction of the Cell Cycle Length by Decreasing G1 Phase and Cell Cycle Reentry Expand Neuronal Progenitor Cells in the Subventricular Zone of Adult Rat after Stroke

“…Stroke transiently switches SVZ cell division from asymmetric to symmetric (Zhang et al, 2004b). To examine whether a transient increase in symmetric division results in augmentation of the fraction of cells that remain in the cell cycle, we measured the proportion of SVZ cells that exit or reenter the cell cycle.…”