A molecular atlas of cell types and zonation in the brain vasculature

  • Nature volume 554, pages 475480 (22 February 2018)
  • doi:10.1038/nature25739
  • Download Citation


Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.

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This study was supported by AstraZeneca AB (C.B., U.L.), the Swedish Research Council (C.B.: 2015-00550; U.L.: K2014-64X-20097-09-5), the European Research Council (C.B.: AdG294556), the Leducq Foundation (C.B., A.K.: 14CVD02), Swedish Cancer Society (C.B.:150735; U.L.:CAN 2016/271), Knut and Alice Wallenberg Foundation (C.B.: 2015.0030), Hjärnfonden (U.L.), Swiss National Science Foundation (A.K.: 31003A_159514/1) and the Synapsis Foundation (A.K.). We thank C. Olsson, H. Leksell, P. Peterson, J. Chmielniakova, K. Gaengel, BioVis (Uppsala), Center for Microscopy and Image Analysis (Zurich) and Eukaryotic Single Cell Genomics facility (Science for Life Laboratory) for technical help, and K. Alitalo, P. Soriano, D. Silver and L. Sorokin for reagents.

Author information

Author notes

    • Michael Vanlandewijck
    •  & Liqun He

    These authors contributed equally to this work.


  1. Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Blickagången 6, SE-141 57 Huddinge, Sweden

    • Michael Vanlandewijck
    • , Elisabeth Raschperger
    •  & Christer Betsholtz
  2. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China

    • Liqun He
  3. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, SE-751 85 Uppsala, Sweden

    • Michael Vanlandewijck
    • , Maarja Andaloussi Mäe
    • , Johanna Andrae
    • , Koji Ando
    • , Khayrun Nahar
    • , Thibaud Lebouvier
    • , Bàrbara Laviña
    • , Leonor Gouveia
    •  & Christer Betsholtz
  4. Department of Cell and Molecular Biology, Karolinska Institutet, Von Eulers väg 3, SE-171 77 Stockholm, Sweden

    • Francesca Del Gaudio
    •  & Urban Lendahl
  5. Inserm U1171, University of Lille, CHU, Memory Center, Distalz, F-59000 Lille, France

    • Thibaud Lebouvier
  6. Department of Bioinformatics, Zhongyuan Union Genetic Technology Co., Ltd., No.45, the 9th East Road, Tianjin Airport Economic Area, Tianjin 300304, China

    • Ying Sun
  7. Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, FI-00014 Helsinki, Finland

    • Markus Räsänen
  8. Division of Neurosurgery, Zürich University Hospital, Zürich University, Zürich, CH-8091, Switzerland

    • Yvette Zarb
    •  & Annika Keller
  9. Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan

    • Naoki Mochizuki
  10. AMED-CREST, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan

    • Naoki Mochizuki


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M.V., L.H., N.M., U.L. and C.B. conceived and designed the project; M.V., M.A.M., J.A., K.A., F.D.G., K.N., T.L., B.L., E.R., L.G., Y.Z., M.R., A.K. and C.B. performed experiments; L.H. performed bioinformatic analysis; L.H. and Y.S. constructed the online database; C.B., L.H. and M.V. analysed the bioinformatic data; C.B. and U.L. wrote the manuscript with substantial input from M.V., L.H., M.A.M., J.A. and K.A. All authors reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Christer Betsholtz.

Reviewer Information Nature thanks D. McDonald and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    This file contains endothelial specific zonated genes.

  2. 2.

    Supplementary Table 2

    This file contains the top 500 endothelial specific differentially expressed genes.

  3. 3.

    Supplementary Table 3

    This file shows differential expression of mural cell specific genes.

  4. 4.

    Supplementary Table 4

    This file contains a list of used antibodies.


  1. 1.

    Localization of perivascular fibroblast-like cells

    A z-stack video taken perpendicular to the midsagittal plane visualizes the location of the pdgfra-H2BGFP positive perivascular cells. Note that, on larger vessels, the cells are inside of the AQP4-positive astrocyte end-feet (Red: AQP4), but outside of the vessel (White: CD31). Capillary-associated pdgfra-H2BGFP positive cells likely represent cells from the oligodendrocyte lineage, and are localized outside of the astrocyte end-feet. See Extended Data Figure 11b for high-resolution still images of the video.


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