Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
PLoS One. 2010 Mar 22;5(3):e9767. doi: 10.1371/journal.pone.0009767.
Focal cerebral ischemia following middle cerebral artery occlusion (MCAO) stimulates a robust cytogenic response from the adult subventricular zone (SVZ) that includes massive proliferation of neural stem/progenitor cells (NSPCs) and cellular migration into the injury area. To begin to explore beneficial roles of NSPCs in this response, we investigated the ability of embryonic and postnatal NSPCs to promote neuronal survival under conditions of in vivo and in vitro ischemia. Intracerebral transplantation of NSPCs attenuated neuronal apoptosis in response to focal ischemia induced by transient MCAO, and prevented neuronal cell death of cortical neurons in response to oxygen-glucose deprivation (OGD) in culture. NSPC-mediated neuroprotection was blocked by the pharmacological inhibitors of vascular endothelial growth factor (VEGF), SU1498 and Flt-1Fc. Embryonic and postnatal NSPCs were both intrinsically resistant to brief OGD exposure, and constitutively expressed both hypoxia-inducible factor 1alpha (HIF-1alpha) transcription factor and its downstream target, VEGF. Genomic deletion of HIF-1alpha by Cre-mediated excision of exon 2 in NSPC cultures resulted in >50% reduction of VEGF production and ablation of NSPC-mediated neuroprotection. These findings indicate that NSPCs promote neuronal survival under ischemic conditions via HIF-1alpha-VEGF signaling pathways and support a role for NSPCs in promotion of neuronal survival following stroke.
大脑中动脉阻塞（MCAO）后引起的局部脑缺血会刺激成年侧脑室下区（SVZ）产生强烈的细胞遗传反应，包括大量神经干细胞/祖细胞（NSPC）的增殖和细胞向损伤区域迁移。为了开始探索 NSPC 在这种反应中的有益作用，我们研究了胚胎和出生后 NSPC 在体内和体外缺血条件下促进神经元存活的能力。NSPC 的脑内移植减弱了短暂 MCAO 诱导的局灶性缺血引起的神经元凋亡，并防止了培养中氧葡萄糖剥夺（OGD）引起的皮质神经元的死亡。NSPC 介导的神经保护作用被血管内皮生长因子（VEGF）的药理学抑制剂 SU1498 和 Flt-1Fc 阻断。胚胎和出生后 NSPC 对短暂的 OGD 暴露都具有内在的抗性，并且组成型表达缺氧诱导因子 1alpha（HIF-1alpha）转录因子及其下游靶标 VEGF。NSPC 培养物中通过 Cre 介导的外显子 2 切除进行的 HIF-1alpha 基因缺失导致 VEGF 产生减少>50%，并消除了 NSPC 介导的神经保护作用。这些发现表明，NSPC 通过 HIF-1alpha-VEGF 信号通路促进缺血条件下神经元的存活，并支持 NSPC 在中风后促进神经元存活中的作用。
