Role of stress-inducible protein-1 in recruitment of bone marrow derived cells into the ischemic brains.
Role of stress-inducible protein-1 in recruitment of bone marrow derived cells into the ischemic brains.
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应激诱导蛋白-1在募集骨髓细胞中的作用，进入缺血性大脑。
DOI：
10.1002/emmm.201202258
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发表时间：
2013-08
影响因子：
11.1
通讯作者：
Shyu, Woei-Cherng
中科院分区：
文献类型：
--
作者：
Lee, Shin-Da;Lai, Ted Weita;Lin, Shinn-Zong;Lin, Chen-Huan;Hsu, Yung-Hsiang;Li, Chi-Yuan;Wang, Hsiao-Jung;Lee, Wei;Su, Ching-Yuan;Yu, Yung-Luen;Shyu, Woei-Cherng
关键词：
应激诱导蛋白-1（STI-1）是细胞朊蛋白（PrPC）的配体，被认为有助于中风后的恢复。STI-1的表达是否受到中风的影响，以及它的信号传导如何促进恢复仍然是难以捉摸的。收集死于缺血性中风的患者的脑切片用于STI-1免疫组织化学。将这些发现与细胞培养物、有或没有PrPC敲除的小鼠和大鼠的结果进行比较。基于这些发现，给予分子和药理学干预以研究潜在的机制，并在实验性中风模型中测试治疗的可能性。STI-1在人类和啮齿动物的缺血性脑中上调。STI-1在体内表达的增加不是细胞类型特异性的，因为它在神经元、神经胶质和内皮细胞中被发现。同样，STI-1表达的增加可以通过体外原代皮层培养物（PCC）中的亚致死性缺氧来模拟，并且似乎是由缺氧诱导因子-1 α（HIF-1α）与STI-1启动子的直接结合引起的。重要的是，这种STI-1信号传导促进骨髓衍生细胞（BMDC）在体外的增殖和迁移以及在体内向缺血性脑的募集，并且增强其信号传导部分地通过向缺血性脑募集BMDC来促进神经恢复。因此，我们的研究结果确定了一种新的机制，缺血性损伤可以触发自我保护机制，以促进恢复。这项工作确定了HIF-1α介导的STI-1和PrPc相互作用的转录导致BMDC在中风患者和中风动物模型中招募到缺血性脑中，突出了新的神经保护可能性。
Stress-inducible protein-1 (STI-1) is the proposed ligand for the cellular prion protein (PrPC), which is thought to facilitate recovery following stroke. Whether STI-1 expression is affected by stroke and how its signalling facilitates recovery remain elusive. Brain slices from patients that died of ischemic stroke were collected for STI-1 immunohistochemistry. These findings were compared to results from cell cultures, mice with or without the PrPC knockout, and rats. Based on these findings, molecular and pharmacological interventions were administered to investigate the underlying mechanisms and to test the possibility for therapy in experimental stroke models. STI-1 was upregulated in the ischemic brains from humans and rodents. The increase in STI-1 expression in vivo was not cell-type specific, as it was found in neurons, glia and endothelial cells. Likewise, this increase in STI-1 expression can be mimicked by sublethal hypoxia in primary cortical cultures (PCCs) in vitro, and appear to have resulted from the direct binding of the hypoxia inducible factor-1α (HIF-1α) to the STI-1 promoter. Importantly, this STI-1 signalling promoted bone marrow derived cells (BMDCs) proliferation and migration in vitro and recruitment to the ischemic brain in vivo, and augmenting its signalling facilitated neurological recovery in part by recruiting BMDCs to the ischemic brain. Our results thus identified a novel mechanism by which ischemic insults can trigger a self-protective mechanism to facilitate recovery. This work identifies HIF-1α-mediated transcription of STI-1 and PrPc interaction as leading to BMDCs recruitment into ischemic brains following stroke in both patients and animal models of stroke, highlighting novel neuroprotective possibilities.
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