Abstract
Background: Adult neural stem cells (NSCs) are present in the rodent ventricular-subventricular zone (V/SVZ) of the lateral ventricles. However, their in vivo role in stroke-induced neurogenesis remains uncertain. Using an anti-mitotic agent (Ara-C) in combination with phenotype markers, we examined NSCs in whole-mount preparation of the lateral ventricle of ischemic brain. Methods and Results: Adult mice (n=28) were used. Focal cerebral ischemia was induced by occluding the right middle cerebral artery. Ara-C was infused on brain surface of mice for 7 days. BrdU was administered to label proliferating cells. Another 6 mice with non-ischemia, non-infusion were also given BrdU labeling as normal control. The architecture of NSCs identified by inhibitor of DNA binding/Differentiation 1 (Id1, a transcription factor)+/GFAP+ in the V/SVZ were examined in whole mount by means of a 3D confocal microscope. In a normal V/SVZ, 3% (at least 4,000 cells counted per each sample) cells were Id1+. Of these Id1+ cells, 16% cells were GFAP+, which were anchored by specialized apical end-feet in the center of the pinwheel of ependymal cells and they often extended basal processes at least 50 -80 um long; none of these cells were BrdU+ after 1h pulse labeling, indicating that these cells are relatively quiescent. However, 69 % of Id1+ cells were Mash+ and Olig2+ and the majority of these cells were BrdU+, indicating that these are active progenitor cells. 1h after termination of infusion, Id1+/Mash+ and Olig2+ cells were eliminated, whereas Id1+/GFAP+ cells in the center of pinwheels were not affected in non-ischemic and ischemic V/SVZ niches. At this time point, there were no actively proliferating cells measured by 1h BrdU pulse labeling. However, by 48h after termination of infusion, there were many proliferating cells with 59% and 75% of BrdU+ cells were Id1+ in non-ischemic and ischemic V/SVZ niches (p<0.05), respectively. In the ischemic V/SVZ niche, in the center of pinwheels the majority of Id1+/BrdU+ cells were GFAP+ . Conclusion: Our in vivo data suggest that adult V/SVZ niche GFAP+/Id1+ astrocytes are “functional quiescent” NSCs. Stroke recruits quiescent NSCs in the V/SVZ niche to an active pool for enhancing the neurogenic process in response to ischemic insult.
Published Version
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