AbstractSubarachnoid hemorrhage (SAH) is one of the most severe type of cerebral strokes, which can cause multiple cellular changes in the brain leading to neuronal injury and neurological deficits. Specifically, SAH can impair adult neurogenesis in the hippocampal dentate gyrus, thus may affecting poststroke neurological and cognitive recovery.

摘要蛛网膜下腔出血（SAH）是最严重的脑卒中类型之一，可引起大脑多种细胞变化，导致神经元损伤和神经功能缺损。具体而言，SAH可损害海马齿状回中的成年神经发生，因此可能影响中风后的神经和认知恢复。

Here, we identified a non-canonical role of milk fat globule epidermal growth factor 8 (MFGE8) in rat brain after experimental SAH, involving a stimulation on adult hippocampal neurogenesis(AHN). Experimental SAH was induced in Sprague-Dawley rats via endovascular perforation, with the in vivo effect of MFGE8 evaluated via the application of recombinant human MFGE8 (rhMFGE8) along with pharmacological interventions, as determined by hemorrhagic grading, neurobehavioral test, and histological and biochemical analyses of neurogenesis related markers.

在这里，我们确定了实验性SAH后乳脂肪球表皮生长因子8（MFGE8）在大鼠大脑中的非典型作用，涉及刺激成年海马神经发生（AHN）。通过血管内穿孔在Sprague-Dawley大鼠中诱导实验性SAH，通过应用重组人MFGE8（rhMFGE8）以及药物干预来评估MFGE8的体内作用，如通过出血分级，神经行为测试以及神经发生相关标志物的组织学和生化分析所确定的。

Results: Levels of the endogenous hippocampal MFGE8 protein, integrin-β3 and protein kinase B (p-Akt) were elevated in the SAH relative to control groups, while that of hippocalcin (HPCA) and cyclin D1 showed the opposite change. Intraventricular rhMGFE8 infusion reversed the decrease in doublecortin (DCX) immature neurons in the DG after SAH, along with improved the short/long term neurobehavioral scores.

结果：与对照组相比，SAH组内源性海马MFGE8蛋白，整合素-β3和蛋白激酶B（p-Akt）水平升高，而海马钙蛋白（HPCA）和细胞周期蛋白D1水平则相反。脑室内rhMGFE8输注逆转了SAH后DG中双皮质素（DCX）未成熟神经元的减少，同时改善了短期/长期神经行为评分。

rhMGFE8 treatment elevated the levels of phosphatidylinositol 3-kinase (PI3K), p-Akt, mammalian target of rapamycin (mTOR), CyclinD1, HPCA and DCX in hippocampal lysates, but not that of integrin β3 and Akt, at 24 hr after SAH. Treatment of integrin β3 siRNA, the PI3K selective inhibitor ly294002 or Akt selective inhibitor MK2206 abolished the effects of rhMGFE8 after SAH.

在SAH后24小时，rhMGFE8处理提高了海马裂解物中磷脂酰肌醇3-激酶（PI3K），p-Akt，哺乳动物雷帕霉素靶标（mTOR），细胞周期蛋白D1，HPCA和DCX的水平，但没有提高整合素β3和Akt的水平。整合素β3 siRNA，PI3K选择性抑制剂ly294002或Akt选择性抑制剂MK2206的处理消除了SAH后rhMGFE8的作用。

In conclusion, MFGE8 is upregulated in the hippocampus in adult rats with reduced granule cell genesis. rhMFGE8.

总之，MFGE8在颗粒细胞发生减少的成年大鼠海马中上调。rhMFGE8。

IntroductionSubarachnoid hemorrhage (SAH) is a common type of hemorrhagic cerebral strokes [1], clinically associated with high mortality and disability [2] or poor prognostic outcome, causing a high socioeconomic burden worldwide [3,4,5]. As with all types of brain stroke, SAH can induce early brain injury (EBI) and delayed brain injury that contribute to poststroke neurological deficits, death or long-term disability.

引言蛛网膜下腔出血（SAH）是一种常见的出血性脑卒中，临床上与高死亡率和残疾（2）或预后不良有关，在全球范围内造成较高的社会经济负担[3，4，5]。与所有类型的脑卒中一样，SAH可诱发早期脑损伤（EBI）和迟发性脑损伤，从而导致卒中后神经功能缺损，死亡或长期残疾。

Notably, cerebral strokes can cause hippocampal neuronal injury, including impairment of adult neurogenesis in the dentate gyrus (DG), which may also relate to poor cognitive recovery among stroke survivors [6, 7].Many animal studies show that adult hippocampal neurogenesis (AHN) plays an essential role in learning, memory and other cognitive functions [6, 8, 9].

值得注意的是，脑卒中可引起海马神经元损伤，包括齿状回（DG）成人神经发生受损，这也可能与卒中幸存者认知恢复不良有关[6，7]。许多动物研究表明，成年海马神经发生（AHN）在学习，记忆和其他认知功能中起着至关重要的作用[6，8，9]。

Residual neural stem cells or progenitor cells at the subgranular zone (SGZ) of the DG proliferate, differentiate and mature, and eventually integrate into neural circuit to perform hippocampus-dependent neurological and cognitive functions [10]. A pivot role of AHN in maintenance or recovery of cognitive functions has been emphasized in many disease conditions such as cerebral stroke, traumatic brain injury and age-related neurodegenerative diseases [6, 7, 11, 12].The milk fat globule-epidermal growth factor 8 (MFGE8) is a soluble glycoprotein characterized structurally by two N-terminal epidermal growth factor (EGF)-like domains.

DG颗粒下区（SGZ）的残留神经干细胞或祖细胞增殖，分化和成熟，并最终整合到神经回路中以执行海马依赖性神经和认知功能（10）。AHN在维持或恢复认知功能中的枢纽作用已在许多疾病中得到强调，例如脑卒中，创伤性脑损伤和与年龄相关的神经退行性疾病[6，7，11，12]。乳脂球表皮生长因子8（MFGE8）是一种可溶性糖蛋白，其结构特征在于两个N端表皮生长因子（EGF）样结构域。

One of the EGF-like domain contains an integrin-binding motif, which binds to integrin β3 on the cell surface of phagocytes. As such, previous studies have focused a principal role of MFGE8 in the process of apoptosis. Recent study shows that MFGE8 is enriched in quiescent neural stem cells [13], and may play a role in mediating neural stem/progenitor cell proliferati.

其中一个EGF样结构域含有整合素结合基序，该基序与吞噬细胞细胞表面的整合素β3结合。因此，以前的研究集中在MFGE8在细胞凋亡过程中的主要作用。最近的研究表明，MFGE8富含静止的神经干细胞，并可能在介导神经干/祖细胞增殖中发挥作用。

Data availability

数据可用性

All data generated or analyzed during this study are included in this published article.

本研究期间生成或分析的所有数据均包含在本文中。

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Download referencesFundingThis study was supported by the National Natural Science Foundation of China (No. 82201483).Author informationAuthor notesThese authors contributed equally: Zhen-Yan Li, Xian Yang.Authors and AffiliationsDepartment of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, ChinaZhen-Yan Li & Yu-Chun ZuoDepartment of Dermatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, ChinaXian YangDepartment of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, ChinaJi-Kai Wang & Fei LiuDepartment of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, 410013, ChinaXiao-Xin YanAuthorsZhen-Yan LiView author publicationsYou can also search for this author in.

下载参考文献资助这项研究得到了国家自然科学基金（No.82201483）的支持。作者信息作者注意到这些作者做出了同样的贡献：李振燕，咸阳。作者和附属机构中南大学湘雅医院神经外科，长沙，410008，中国湖南中医药大学第一医院皮肤科，长沙，410007，中国西安杨中山大学第五附属医院神经外科，珠海，519000，中国王季凯和刘飞中南大学湘雅医学院解剖与神经生物学系，长沙，410013，中国YanaXiao YanAuthorsZhen Yan LiView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsYZ, ZL performed study concept and design; YZ, JW and XY performed the experiments; ZL, JW and XY collected and analyzed the data; YZ and ZL drafted the manuscript; XXY and FL review and revision of the paper. All authors read and approved the final paper.Corresponding authorCorrespondence to.

PubMed Google ScholarContributionsYZ，ZL进行了研究概念和设计；YZ，JW和XY进行了实验；ZL，JW和XY收集并分析了数据；YZ和ZL起草了手稿；XXY和FL审查和修订论文。所有作者都阅读并批准了最终论文。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleLi, ZY., Yang, X., Wang, JK. et al. MFGE8 promotes adult hippocampal neurogenesis in rats following experimental subarachnoid hemorrhage via modifying the integrin β3/Akt signaling pathway.

转载和许可本文引用本文Li，ZY。，杨，X，王，JK。MFGE8通过修饰整合素β3/Akt信号通路促进实验性蛛网膜下腔出血后大鼠成年海马神经发生。

Cell Death Discov. 10, 359 (2024). https://doi.org/10.1038/s41420-024-02132-xDownload citationReceived: 17 February 2024Revised: 28 July 2024Accepted: 01 August 2024Published: 11 August 2024DOI: https://doi.org/10.1038/s41420-024-02132-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

细胞死亡发现。10359（2024）。https://doi.org/10.1038/s41420-024-02132-xDownload引文收到日期：2024年2月17日修订日期：2024年7月28日接受日期：2024年8月1日发布日期：2024年8月11日OI：https://doi.org/10.1038/s41420-024-02132-xShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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