人类大脑发育、成年和疾病血管系统的单细胞图谱-动脉网

Single-cell atlas of the human brain vasculature across development, adulthood and disease

Nature 等信源发布 2024-07-09 23:27

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AbstractA broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature.

摘要广泛的脑部病理严重依赖于脉管系统，脑血管疾病是全球死亡的主要原因。然而，人脑脉管系统的细胞和分子结构仍未完全了解1。在这里，我们对来自68名人类胎儿和成年患者的117个样品中的606380个新鲜分离的内皮细胞，血管周围细胞和其他组织来源的细胞进行了单细胞RNA测序分析，以构建发育中的胎儿，成人对照和患病人脑血管系统的分子图谱。

We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature.

我们确定了健康胎儿和成人大脑脉管系统的广泛分子异质性，以及五种血管依赖性中枢神经系统（CNS）病理，包括脑肿瘤和脑血管畸形。我们确定了动静脉分化的改变和重新激活的胎儿以及患病脉管系统中保守的失调基因和途径。

Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks.

病理性内皮细胞表现出中枢神经系统特异性的丧失，并显示MHC II类分子的上调，表明中枢神经系统内皮细胞的非典型特征。细胞间相互作用分析预测内皮细胞与血管周围细胞配体-受体的大量串扰，包括免疫相关和血管生成途径，从而揭示了内皮在脑神经血管单元信号网络中的核心作用。

Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies..

我们的单细胞大脑图谱提供了对发育中的，成人/对照和患病的人脑血管系统的分子结构和异质性的见解，并为未来的研究提供了有力的参考。。

MainThe brain vasculature is important for both the proper functioning of the normal brain as well as for a variety of vascular-dependent CNS pathologies such as brain tumours, brain vascular malformations, stroke and neurodegenerative diseases1,2,3,4,5,6,7,8,9. A better understanding of the underlying cellular and molecular mechanisms and architecture of the vasculature during brain development, in the healthy adult brain, as well as in vascular-dependent brain diseases, has broad implications for both the biological understanding as well as the therapeutic targeting of the pathological brain vasculature10,11,12,13,14,15.

Main脑血管系统对于正常大脑的正常功能以及各种血管依赖性中枢神经系统疾病（如脑肿瘤，脑血管畸形，中风和神经退行性疾病）都很重要1,2,3,4,5,6,7,8,9。更好地了解大脑发育过程中，健康成人大脑以及血管依赖性脑部疾病中血管系统的潜在细胞和分子机制和结构，对生物学理解以及治疗靶向都有广泛的意义。病理性脑血管10,11,12,13,14,15。

Vascular growth and network formation, involving endothelial cells (ECs) and other cells of the neurovascular unit (NVU), are highly dynamic during brain development, almost quiescent in the healthy adult brain and reactivated in a variety of angiogenesis-dependent brain pathologies, including brain tumours and brain vascular malformations3,7,16,17,18,19,20,21, thereby activating ECs and perivascular cells (PVCs) of the NVU and other tissue-derived cells (hereafter collectively referred to as PVCs).

涉及内皮细胞（EC）和神经血管单元（NVU）的其他细胞的血管生长和网络形成在大脑发育过程中是高度动态的，在健康的成年大脑中几乎静止，并在各种血管生成依赖性脑病理中重新激活，包括脑肿瘤和脑血管畸形3,7,16,17,18,19,20,21，从而激活NVU和其他组织来源细胞（以下统称为PVC）的EC和血管周围细胞（PVC）。

However, it is unclear which molecular signalling cascades are reactivated and how they regulate brain tumour and brain vascular malformation vascularization and growth.The CNS vasculature has unique features such as the blood–brain barrier (BBB) and the NVU22,23,24. During development, various CNS-specific and general signalling pathways drive CNS angiogenesis3,7,23,25,26,27.

然而，尚不清楚哪些分子信号级联被重新激活，以及它们如何调节脑肿瘤和脑血管畸形的血管形成和生长。中枢神经系统脉管系统具有独特的功能，例如血脑屏障（BBB）和NVU22,23,24。在发育过程中，各种中枢神经系统特异性和一般信号通路驱动中枢神经系统血管生成3,7,23,25,26,27。

The brain vasculature also displays an arteriovenous (AV) endothelial hierarchy similar to peripheral vascular beds28,29,30. Developmentally regulated signalling axes in ECs are thought to contribute to the establishment of CNS-specific properties as well as AV specification of the e.

。EC中发育调节的信号轴被认为有助于建立CNS特异性特性以及e的AV规范。

Data availability

数据可用性

All data are now accessible under Gene Expression Omnibus accession number GSE256493. An interactive website is available at https://waelchli-lab-human-brain-vasculature-atlas.ethz.ch, https://brain-vasc.cells.ucsc.edu and https://cellxgene.cziscience.com/collections/c95ca269-68a7-47c5-82db-da227f31b598 on which the data can visualized and downloaded..

现在可以在Gene Expression Omnibus登录号GSE256493下访问所有数据。交互式网站位于https://waelchli-lab-human-brain-vasculature-atlas.ethz.ch，https://brain-vasc.cells.ucsc.edu和https://cellxgene.cziscience.com/collections/c95ca269-68a7-47c5-82db-da227f31b598数据可以在其上可视化和下载。。

Code availability

代码可用性

Most of our analyses are standard workflows and we have now deposited the source code at GitHub (https://github.com/Waelchli-lab/Single-cell-atlas-of-the-human-brain-vasculature-accross-development-adulthood-and-disease) to improve reproducibility our results. The generated Seurat objects of FACS-sorted (CD31+CD45−) ECs for the individual entities can be downloaded from https://doi.org/10.5281/zenodo.10058183, and for the overall merges from https://doi.org/10.5281/zenodo.10057779.

我们的大多数分析都是标准的工作流程，现在我们已经将源代码存放在GitHub(https://github.com/Waelchli-lab/Single-cell-atlas-of-the-human-brain-vasculature-accross-development-adulthood-and-disease)为了提高重复性，我们的结果。为各个实体生成的FACS排序（CD31+CD45-）EC的Seurat对象可以从https://doi.org/10.5281/zenodo.10058183，以及从https://doi.org/10.5281/zenodo.10057779.

The generated Seurat objects of unsorted ECs and PVCs for individual entities can be downloaded from https://doi.org/10.5281/zenodo.10058371, and for the overall merges from https://doi.org/10.5281/zenodo.10058563. The generated Monocle 3 CDS pseudotime objects of FACS-sorted (CD31+CD45−) ECs can be downloaded from https://doi.org/10.5281/zenodo.10058766.

为单个实体生成的未排序EC和PVC的Seurat对象可以从https://doi.org/10.5281/zenodo.10058371，以及从https://doi.org/10.5281/zenodo.10058563.生成的FACS分选（CD31+CD45-）EC的Monocle 3 CDS伪时间对象可以从https://doi.org/10.5281/zenodo.10058766.

The generated diffusion map objects of FACS-sorted (CD31+CD45−) ECs can be downloaded from https://doi.org/10.5281/zenodo.10060876. The generated RNA velocity objects of FACS-sorted (CD31+CD45−) ECs of individual pathological entities can be downloaded from https://doi.org/10.5281/zenodo.10065659; the fetal and adult/control brains from https://doi.org/10.5281/zenodo.10066390; the overall merge of brain tumours from https://doi.org/10.5281/zenodo.10066538; and the overall merge of pathological entities from https://doi.org/10.5281/zenodo.10066703..

生成的FACS分选（CD31+CD45-）EC的扩散图对象可以从https://doi.org/10.5281/zenodo.10060876.生成的单个病理实体的FACS分选（CD31+CD45-）EC的RNA速度对象可以从https://doi.org/10.5281/zenodo.10065659；胎儿和成人/对照大脑https://doi.org/10.5281/zenodo.10066390；来自大脑肿瘤的整体合并https://doi.org/10.5281/zenodo.10066538；以及来自https://doi.org/10.5281/zenodo.10066703..

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Download referencesAcknowledgementsWe thank N. Krayenbühl, M. Germans, O. Bozinov, P. Bijlenga, P.-Y. Dietrich and V. Dutoit for help with the human adult tissue asservation; the donors and the staff at the RCWIH Biobank, the Lunenfeld-Tanenbaum Research Institute, the Mount Sinai Hospital/UHN Department of Obstetrics and Gynaecology, and Maximilian Niit for help with the human fetal specimen asservation, preparation and IHC staining (https://biobank.lunenfeld.ca); E.

下载参考文献致谢我们感谢N.Krayenbühl，M.Germans，O.Bozinov，P.Bijlenga，P.-Y.Dietrich和V.Dutoit对成人组织保存的帮助；RCWIH生物库，Lunenfeld Tanenbaum研究所，西奈山医院/UHN妇产科以及Maximilian Niit的捐赠者和工作人员为人类胎儿标本的保存，制备和IHC染色提供了帮助(https://biobank.lunenfeld.ca)；E。

Speck and the members of the Flow Cytometry Facility, Krembil Discovery Tower, University Health Network for help with the FACS sorting; G. Basi, J. Cirlan, C. Dumrese and M. Kisielow for help with the scRNA-seq experiments; A. M. Sababi and M. M. Saad for help with the computational analysis; J. L.

Speck和大学健康网络Krembil Discovery Tower流式细胞仪设施的成员帮助进行FACS分选；G、；A、 M.Sababi和M.M.Saad帮助进行计算分析；J、 L。

Gorman for help with the IMC experiments; the members of the University Health Network, Laboratory Medicine-Pathology Research Program and Melanie Peralta for help with adult specimen preparation and IHC staining; N. C. Ji for help with the illustrations; A. Thomson for help with English proofreading; A.

戈尔曼帮助IMC实验；大学健康网络，实验医学病理学研究计划和Melanie Peralta的成员帮助进行成人标本制备和IHC染色；N、 C.Ji为插图提供帮助；A、汤姆森帮助英语校对；答：。

Keller, F. Kern, T. Nowakowski, E. Winkler, M. Kellis, N. Sun, A. Regev, G. Eraslan, F. J. Theis, J. Shin, M. Prinz, R. Sankowski, R. Adams, S. Teichmann, L. Yang, A. Maria Cujba and N. Huang for their scientific inputs and advice regarding computational integration methods, the covariates age and sex, and overall discussion of our manuscript and figures.

Keller，F。Kern，T。Nowakowski，E。Winkler，M。Kellis，N。Sun，A。Regev，G。Eraslan，F。J。Theis，J。Shin，M。Prinz，R。Sankowski，R。Adams，S。Teichmann，L。Yang，A。Maria Cujba和N。Huang，感谢他们关于计算积分方法，协变量年龄和性别以及我们手稿和数字的整体讨论的科学投入和建议。

We acknowledge the following financial support for the research, and/or publication of this Article: T.W. was supported by the OPO Foundation, the Swiss Cancer Research foundation (KFS-3880-02-2016-R, KFS-4758-02-2019-R), the Stiftung zur Krebsbekämpfung, the Kurt und Senta Herrmann Foundation, Forschungskredit of the University of Zurich, the .

我们感谢以下对本文研究和/或发表的财政支持：T.W.得到了OPO基金会，瑞士癌症研究基金会（KFS-3880-02-2016-R，KFS-4758-02-2019-R），Stiftung zur Krebsbekämpfung，Kurt und Senta Herrmann Foundation，苏黎世大学Forschungskredit的支持。

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PubMed Google ScholarContributionsT.W. had the idea for the study. T.W. and I.R. conceived the study. T.W. designed the experiments, wrote the manuscript, analysed the data, designed the figures and made the figures with M.G. with the help of M.S.; I.R., T.W., L.R., K.S., M.B., P.K., G.Z.

PubMed谷歌学术贡献者。W、有这个研究的想法。T、 W.和I.R.构思了这项研究。T、 W.设计实验，撰写手稿，分析数据，设计数字，并在M.S.的帮助下与M.G.一起制作数字。；一、 R.，T.W.，L.R.，K.S.，M.B.，P.K.，G.Z。

and T.V. acquired the tissue. M.G., M.S., S.S. and S.V. performed the cell isolation experiments. T.W. and K.F. developed the initial isolation experiments. M.G. (majority of the analysis), M.S., H.Z., D.R.G. and H.R. performed the single-cell data processing and analysed the data with T.W.; T.W. and G.D.B.

T.V.获得了组织。M、。T、 W.和K.F.开发了初始隔离实验。M、 G.（大部分分析），M.S.，H.Z.，D.R.G.和H.R.进行了单细胞数据处理，并用T.W.分析了数据。；T、 W.和G.D.B。

supervised the data analysis and interpreted data. R.S. and T.K. helped with single-cell data processing. M.G., M.S. and G.D.B. developed the computational methods with the help of T.W.; S.T., S.S., R.W. and K.Y. performed the IF stainings and RNA scope experiments, and S.T., R.W., K.Y., M.G., M.S., J.E.F.

监督数据分析和解释数据。R、 S.和T.K.帮助进行单细胞数据处理。M、 G.，M.S.和G.D.B.在T.W.的帮助下开发了计算方法。；S、 T.，S.S.，R.W.和K.Y.进行了IF染色和RNA范围实验，S.T.，R.W.，K.Y.，M.G.，M.S.，J.E.F。

and T.W. analysed and interpreted the data. M.S., R.W., J.E.F. and T.W. selected the final IF images. A.D. E.L.Y.C. and H.W.J. performed the IMC staining, and A.D., M.S., H.W.J. and T.W. analysed and interpreted the data. M.S., H.W.J. and T.W. selected the final IMC images. T.W., I.R., G.D.B. and P.P.M.

和T.W.分析并解释了数据。M、 S.，R.W.，J.E.F.和T.W.选择了最终的IF图像。A、 D.E.L.Y.C.和H.W.J.进行了IMC染色，A.D.，M.S.，H.W.J.和T.W.分析并解释了数据。M、 S.，H.W.J.和T.W.选择了最终的IMC图像。T、 W.，I.R.，G.D.B.和P.P.M。

acquired funding. T.W., P.P.M., I.R. and G.D.B. edited the final version of the manuscript. M.G., M.S. and J.B. helped edit the manuscript. P.P.M., K.D.B., J.E.F., M.L.S., P.B.D., P.C., V.T., G.Z., T.V., I.R. and G.D.B. provided critical inputs to the manuscript. T.W. supervised all of the research.

获得资金。T、 W.，P.P.M.，I.R.和G.D.B.编辑了手稿的最终版本。M、 G.，M.S.和J.B.帮助编辑了手稿。P、 P.M.，K.D.B.，J.E.F.，M.L.S.，P.B.D.，P.C.，V.T.，G.Z.，T.V.，I.R.和G.D.B.为手稿提供了关键的输入。T、 W.监督了所有的研究。

All of the authors read and approved the final manuscript.Corresponding authorCorrespondence to.

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托马斯·沃克利。道德宣言

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The authors declare no competing interests.

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Nature thanks Konstantin Khodosevich and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

《自然》杂志感谢康斯坦丁·霍多塞维奇（KonstantinKhodosevich）和另一位匿名审稿人对这项工作的同行评审做出的贡献。同行评审报告可供查阅。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Construction of a molecular single-cell atlas of the human brain vasculature across development, adulthood and disease and of the fetal peripheral vasculature - studied entities and inter-tissue heterogeneity.Figure shows studied entities and inter-tissue heterogeneity of sorted vascular endothelial cells.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据图和表扩展数据图1构建跨越发育，成年和疾病以及胎儿外周脉管系统的人脑脉管系统的分子单细胞图谱-研究实体和组织间异质性。图显示了分选的血管内皮细胞的研究实体和组织间异质性。

a,b, Scheme of the different tissue types present in the study with respective sample/patient numbers of fetal (a) and adult (b) origins. c, Piechart showing relative abundance and percentage of ECs from each tissue collected. d, Composite UMAP plots of sorted and in silico-quality checked (ECs, coloured by tissue of origin.

a、 b，研究中存在的不同组织类型的方案，以及胎儿（a）和成人（b）起源的各自样本/患者数量。c、 Piechart显示收集的每个组织中EC的相对丰度和百分比。d、分类和计算机质量检查的复合UMAP图（EC，由起源组织着色。

e, Violin plots of the expression of the top marker genes of each tissue type, percentage of cells expressing the marker gene is indicated on the right. f, Endothelial cells transcriptome correlation heatmap and hierarchical clustering of all tissues analysed. g, Dotplot heatmap of the fetal brain vs fetal periphery endothelial signature.

e、每种组织类型的顶部标记基因表达的小提琴图，右侧显示了表达标记基因的细胞百分比。f、内皮细胞转录组相关性热图和所有组织的分层聚类分析。g、胎儿大脑与胎儿外周内皮特征的点图热图。

h, Expression heatmap of top ranking marker genes in the indicated tissues. Colour scale: red, high expression; white, intermediate expression; blue, low expression.Extended Data Fig. 2 Validation of angiogenic and EndoMT markers in vascular ECs of the fetal, adult and pathological brain vasculature using RNAscope, IF and IMC.a-g, Volcano plots showing the differential expression analysis comparing endothelial cells from adult/control brains (left) and the indicated entity (right) (Wald test, Benjamini Hochberg correction; P-value < 0.05 and log2FC ≥ 0.25 coloured significant in red, PLVAP dot is coloured b.

h、指定组织中排名最高的标记基因的表达热图。色阶：红色，高表达；白色，中间表达；蓝色，表情低沉。扩展数据图2使用RNAscope，IF和IMC.a-g验证胎儿，成人和病理性脑血管系统的血管内皮细胞中的血管生成和EndoMT标记，火山图显示差异表达分析，比较来自成人/对照大脑的内皮细胞（左）和指示的实体（右）（Wald检验，Benjamini-Hochberg校正；P值<0.05，log2FC≥0.25红色显着，PLVAP点为b色。

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Reprints and permissionsAbout this articleCite this articleWälchli, T., Ghobrial, M., Schwab, M. et al. Single-cell atlas of the human brain vasculature across development, adulthood and disease.

转载和许可本文引用本文Wälchli，T.，Ghobrial，M.，Schwab，M。等人的《跨发育，成年和疾病的人脑血管系统单细胞图谱》。

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