Single-Cell RNA Sequencing and Spatial Transcriptomics Reveal Pathogenesis of Meningeal Lymphatic Dysfunction after Experimental Subarachnoid Hemorrhage.
Single-Cell RNA Sequencing and Spatial Transcriptomics Reveal Pathogenesis of Meningeal Lymphatic Dysfunction after Experimental Subarachnoid Hemorrhage.
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单细胞RNA测序和空间转录组学揭示实验性蛛网膜下腔出血后脑膜淋巴功能障碍的发病机制。
DOI：
10.1002/advs.202301428
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发表时间：
2023-07
期刊：
影响因子：
15.1
通讯作者：
Zhang, Jianmin
中科院分区：
文献类型：
--
作者：
Wang, Xiaoyu;Zhang, Anke;Yu, Qian;Wang, Zelin;Wang, Junjie;Xu, Penglei;Liu, Yibo;Lu, Jianan;Zheng, Jingwei;Li, Huaming;Qi, Yangjian;Zhang, Jiahao;Fang, Yuanjian;Xu, Shenbin;Zhou, Jingyi;Wang, Kaikai;Chen, Sheng;Zhang, Jianmin
关键词：
蛛网膜下腔出血(SAH)是一种致死率和致残率较高的卒中亚型。脑膜淋巴管(MLV)是新近发现的一种颅内液体转运系统，SAH后可将渗出的红细胞从脑脊液中排入颈深部淋巴结。然而，许多研究报道，MLV的结构和功能在一些中枢神经系统疾病中受到损害。蛛网膜下腔出血是否可引起MLVS损伤及其机制尚不清楚。在此，我们应用单细胞RNA测序和空间转录，结合体内和体外实验，研究SAH后MLV的细胞、分子和空间模式的变化。首先，证明了SAH可引起MLVS损伤。然后，通过对测序数据的生物信息学分析，发现血栓反应蛋白1(THBS1)和S100A6与SAH的预后密切相关。此外，THBS1-CD47配体-受体对通过调节STAT3/Bcl-2信号通路在脑膜淋巴管内皮细胞的凋亡中发挥关键作用。这些结果首次显示了SAH后损伤的MLV的图景，并通过破坏THBS1和CD47的相互作用提供了一种基于MLVS保护的SAH的潜在治疗策略。本研究首次将单细胞RNA测序和空间转录学相结合，对蛛网膜下腔出血(SAH)后脑膜淋巴管(MLV)组织中不同细胞团的组成和变化进行了全面的研究。血小板反应素1-CD47配体-受体相互作用可诱导脑膜淋巴管内皮细胞凋亡，这可能是SAH后MLVS损伤的最初原因。
Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and disability rate. Meningeal lymphatic vessels (mLVs) are a newly discovered intracranial fluid transport system and are proven to drain extravasated erythrocytes from cerebrospinal fluid into deep cervical lymph nodes after SAH. However, many studies have reported that the structure and function of mLVs are injured in several central nervous system diseases. Whether SAH can cause mLVs injury and the underlying mechanism remain unclear. Herein, single‐cell RNA sequencing and spatial transcriptomics are applied, along with in vivo/vitro experiments, to investigate the alteration of the cellular, molecular, and spatial pattern of mLVs after SAH. First, it is demonstrated that SAH induces mLVs impairment. Then, through bioinformatic analysis of sequencing data, it is discovered that thrombospondin 1 (THBS1) and S100A6 are strongly associated with SAH outcome. Furthermore, the THBS1‐CD47 ligand‐receptor pair is found to function as a key role in meningeal lymphatic endothelial cell apoptosis via regulating STAT3/Bcl‐2 signaling. The results illustrate a landscape of injured mLVs after SAH for the first time and provide a potential therapeutic strategy for SAH based on mLVs protection by disrupting THBS1 and CD47 interaction. This study integrates single‐cell RNA sequencing and spatial transcriptomics to comprehensively characterize the composition and alterations of different cell clusters in meningeal lymphatic vessels (mLVs) tissues after subarachnoid hemorrhage (SAH) in mice models for the first time. Thrombospondin 1‐CD47 ligand‐receptor interaction is proven to induce meningeal lymphatic endothelial cell apoptosis, which might be the initial reason for mLVs injury after SAH.
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