GRP78 Promotes Neural Stem Cell Antiapoptosis and Survival in Response to Oxygen-Glucose Deprivation (OGD)/Reoxygenation through PI3K/Akt, ERK1/2, and NF-κB/p65 Pathways.
GRP78 Promotes Neural Stem Cell Antiapoptosis and Survival in Response to Oxygen-Glucose Deprivation (OGD)/Reoxygenation through PI3K/Akt, ERK1/2, and NF-κB/p65 Pathways.
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DOI：
10.1155/2018/3541807
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发表时间：
2018
影响因子：
--
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Liu Q;Li Y;Zhou L;Li Y;Xu P;Liu X;Lv Q;Li J;Guo H;Cai H;Sun R;Liu X
当脑损伤发生时，位于成年大鼠脑室下区（subventricular zone，SVZ）和颗粒下区（subgranular zone，SGZ）的内源性神经干细胞（neural stem cells，NSCs）受到缺血/再灌注损伤，发生细胞凋亡和死亡，然后被诱导迁移到损伤点，分化为成熟的神经细胞进行损伤细胞的替代。虽然促进抗凋亡和NSC存活对神经再生至关重要，但其机制尚未阐明。本研究建立了体外培养的神经干细胞缺氧/复氧模型，检测了葡萄糖调节蛋白78（glucose-regulated protein 78，GRP 78）参与神经干细胞凋亡的情况，并通过siRNA转染GRP 78的方法，观察了缺氧/复氧对神经干细胞凋亡的影响，发现缺氧/复氧可诱导PI 3 K/Akt、ERK 1/2和NF-κB/p65的激活，并抑制了神经干细胞凋亡。进一步的研究表明，分别用PI 3 K/Akt或ERK 1/2抑制剂阻断GRP 78上调，而NF-κB的抑制很少影响OGD/复氧对GRP 78的诱导。结果表明，GRP 78-PI 3 K/Akt和GRP 78-ERK 1/2的双向调节以及GRP 78-NF-κB/p65的单向信号转导对OGD/复氧后NSC存活的影响。总之，我们发现GRP 78通过PI 3 K/Akt、ERK 1/2和NF-κB/p65介导信号转导，从而导致抗凋亡和缺血性卒中的NSC存活。我们的发现为神经干细胞中GRP 78的存在提供了新的证据，并为神经干细胞从缺血性卒中中存活提供了新的信号机制。
When brain injury happens, endogenous neural stem cells (NSCs) located in the adult subventricular zone (SVZ) and subgranular zone (SGZ) are attacked by ischemia/reperfusion to undergo cellular apoptosis and death before being induced to migrate to the lesion point and differentiate into mature neural cells for damaged cell replacement. Although promoting antiapoptosis and NSC survival are critical to neuroregeneration, the mechanism has yet been elucidated clearly. Here in this study, we established an in vitro oxygen-glucose deprivation (OGD)/reoxygenation model on NSCs and detected glucose-regulated protein 78 (GRP78) involved in apoptosis, while in the absence of GRP78 by siRNA transfection, OGD/reoxygenation triggered PI3K/Akt, ERK1/2, and NF-κB/p65 activation, and induced NSC apoptosis was attenuated. Further investigation, respectively, with the inhibitor of PI3K/Akt or ERK1/2 demonstrated a blockage on GRP78 upregulation, while the inhibition of NF-κB rarely affected GRP78 induction by OGD/reoxygenation. The results indicated the bidirectional regulations of GRP78-PI3K/Akt and GRP78-ERK1/2 and the one-way signalling transduction through GRP78 to NF-κB/p65 on NSC survival from OGD/reoxygenation. In conclusion, we found that GRP78 mediated the signalling cross talk through PI3K/Akt, ERK1/2, and NF-κB/p65, which leads to antiapoptosis and NSC survival from ischemic stroke. Our finding gives a new evidence of GRP78 in NSCs as well as a new piece of signalling mechanism elucidation to NSC survival from ischemic stroke.
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