Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice
Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice
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DOI：
10.1093/brain/aws259
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发表时间：
2012-11-01
期刊：
影响因子：
14.5
通讯作者：
Chan, Pak H.
中科院分区：
文献类型：
--
作者：
Sakata, Hiroyuki;Narasimhan, Purnima;Chan, Pak H.
神经干细胞移植为卒中提供了一种很有前途的治疗方法。然而，由于移植后移植细胞大量死亡，以及其组织修复能力不足，其疗效可能有限。白介素6是一种促炎细胞因子，参与了多种神经系统疾病的发病机制。矛盾的是，白介素6通过激活信号转导和转录激活子3促进促进生存的信号通路。在这项研究中，我们研究了用白介素6对神经干细胞进行细胞重编程是否有助于细胞移植治疗缺血性卒中的有效性。取胎鼠脑室下区神经干细胞，在体外用白介素6进行预处理，在大脑中动脉短暂性阻断后6h或7d移植到小鼠脑内。IL-6预适应通过信号转导和转录激活因子3上调线粒体主要抗氧化酶--锰超氧化物歧化酶的表达，保护移植神经干细胞免受缺血再灌注损伤。此外，白介素6预适应通过激活信号转导和转录激活子3，诱导神经干细胞分泌血管内皮生长因子，从而促进缺血脑血管生成。此外，与未经白细胞介素6预处理的神经干细胞相比，移植白细胞介素6预适应的神经干细胞显著地缩小了梗塞面积并改善了神经功能。移植前将信号转导和转录激活子3小干扰RNA导入神经干细胞，可消除白介素6对缺血损伤的改善作用。这些结果表明，白细胞介素6对缺血再灌注损伤后的神经干细胞进行预适应，使其耐受氧化应激，并通过激活信号转导和转录激活因子3来诱导血管生成，是提高细胞移植治疗缺血性卒中疗效的一种简单而有益的方法。
Transplantation of neural stem cells provides a promising therapy for stroke. Its efficacy, however, might be limited because of massive grafted-cell death after transplantation, and its insufficient capability for tissue repair. Interleukin 6 is a pro-inflammatory cytokine involved in the pathogenesis of various neurological disorders. Paradoxically, interleukin 6 promotes a pro-survival signalling pathway through activation of signal transducer and activator of transcription 3. In this study, we investigated whether cellular reprogramming of neural stem cells with interleukin 6 facilitates the effectiveness of cell transplantation therapy in ischaemic stroke. Neural stem cells harvested from the subventricular zone of foetal mice were preconditioned with interleukin 6 in vitro and transplanted into mouse brains 6 h or 7 days after transient middle cerebral artery occlusion. Interleukin 6 preconditioning protected the grafted neural stem cells from ischaemic reperfusion injury through signal transducer and activator of transcription 3-mediated upregulation of manganese superoxide dismutase, a primary mitochondrial antioxidant enzyme. In addition, interleukin 6 preconditioning induced secretion of vascular endothelial growth factor from the neural stem cells through activation of signal transducer and activator of transcription 3, resulting in promotion of angiogenesis in the ischaemic brain. Furthermore, transplantation of interleukin 6-preconditioned neural stem cells significantly attenuated infarct size and improved neurological performance compared with non-preconditioned neural stem cells. This interleukin 6-induced amelioration of ischaemic insults was abolished by transfecting the neural stem cells with signal transducer and activator of transcription 3 small interfering RNA before transplantation. These results indicate that preconditioning with interleukin 6, which reprograms neural stem cells to tolerate oxidative stress after ischaemic reperfusion injury and to induce angiogenesis through activation of signal transducer and activator of transcription 3, is a simple and beneficial approach for enhancing the effectiveness of cell transplantation therapy in ischaemic stroke.