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Single-cell dissection of the human cerebrovasculature in health and disease

Francisco J. Garcia, Na Sun, Hyeseung Lee, Brianna Godlewski, Kyriaki Galani, Julio Mantero, David A. Bennett, View ORCID ProfileMustafa Sahin, Manolis Kellis, Myriam Heiman
doi: https://doi.org/10.1101/2021.04.26.440975
Francisco J. Garcia
1Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA
2Picower Institute for Learning and Memory, Cambridge, MA, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Na Sun
3Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA
4MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Hyeseung Lee
2Picower Institute for Learning and Memory, Cambridge, MA, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Brianna Godlewski
5Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA
6Department of Neurology, Harvard Medical School, Boston, MA, USA
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Kyriaki Galani
3Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA
4MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Julio Mantero
3Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA
4MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
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David A. Bennett
8Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
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Mustafa Sahin
5Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA
6Department of Neurology, Harvard Medical School, Boston, MA, USA
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  • ORCID record for Mustafa Sahin
Manolis Kellis
3Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA
4MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • For correspondence: mheiman@mit.edu manoli@mit.edu
Myriam Heiman
1Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA
2Picower Institute for Learning and Memory, Cambridge, MA, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • For correspondence: mheiman@mit.edu manoli@mit.edu
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Summary

Despite the importance of the blood-brain barrier in maintaining normal brain physiology and in understanding neurodegeneration and CNS drug delivery, human cerebrovascular cells remain poorly characterized due to their sparsity and dispersion. Here, we perform the first single-cell characterization of the human cerebrovasculature using both ex vivo fresh-tissue experimental enrichment and post mortem in silico sorting of human cortical tissue samples. We capture 31,812 cerebrovascular cells across 17 subtypes, including three distinct subtypes of perivascular fibroblasts as well as vasculature-coupled neurons and glia. We uncover human-specific expression patterns along the arteriovenous axis and determine previously uncharacterized cell type-specific markers. We use our newly discovered human-specific signatures to study changes in 3,945 cerebrovascular cells of Huntington’s disease patients, which reveal an activation of innate immune signaling in vascular and vasculature-coupled cell types and the concomitant reduction to proteins critical for maintenance of BBB integrity. Finally, our study provides a comprehensive resource molecular atlas of the human cerebrovasculature to guide future biological and therapeutic studies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵9 co-first authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 27, 2021.
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Single-cell dissection of the human cerebrovasculature in health and disease
Francisco J. Garcia, Na Sun, Hyeseung Lee, Brianna Godlewski, Kyriaki Galani, Julio Mantero, David A. Bennett, Mustafa Sahin, Manolis Kellis, Myriam Heiman
bioRxiv 2021.04.26.440975; doi: https://doi.org/10.1101/2021.04.26.440975
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Single-cell dissection of the human cerebrovasculature in health and disease
Francisco J. Garcia, Na Sun, Hyeseung Lee, Brianna Godlewski, Kyriaki Galani, Julio Mantero, David A. Bennett, Mustafa Sahin, Manolis Kellis, Myriam Heiman
bioRxiv 2021.04.26.440975; doi: https://doi.org/10.1101/2021.04.26.440975

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