Ischemia induced neural stem cell proliferation and differentiation in neonatal rat involved vascular endothelial growth factor and transforming growth factor-beta pathways.

Brain ischemia is a leading cause of mortality and morbidity in premature infants. Knowing the fate of neural stem cells in the subventricular zone (SVZ) after ischemia and the mechanisms that determine this fate would be useful in manipulating neural stem cell proliferation and differentiation and possibly in reversing ischemic damage. We sought to identify the genes involved in the proliferation and differentiation of neural stem cells after exposure to ischemia in a 3-day-old rat model that approximates ischemia in premature infants. Proliferating cells were labeled by bromodeoxyuridine (BrdU) through intraperitoneal injection. Using immunfluorescence assays, we observed the proliferation and differentiation of neural stem cells. Genes were identified with GeneChip and real-time quantitative polymerase chain reaction analysis. Ischemic rats had more BrdU-positive cells in the SVZ at all four time points and more neural stem cells differentiation into neurons, astrocytes, and oligodendrocytes. GeneChip analysis showed a 3- to 10-fold increase in the mRNA expression of vascular endothelial growth factor, transforming growth factor-beta, and their receptors in the SVZ. PCR assays and Western blot analyses confirmed these results, indicating that vascular endothelial growth factor and transforming growth factor-beta might be two of the factors that involve post-ischemic neural stem cell proliferation and differentiation.