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Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain

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Abstract

Age-related phenotypic changes of cerebromicrovascular endothelial cells lead to dysregulation of cerebral blood flow and blood-brain barrier disruption, promoting the pathogenesis of vascular cognitive impairment (VCI). In recent years, endothelial cell senescence has emerged as a potential mechanism contributing to microvascular pathologies opening the avenue to the therapeutic exploitation of senolytic drugs in preclinical studies. However, difficulties with the detection of senescent endothelial cells in wild type mouse models of aging hinder the assessment of the efficiency of senolytic treatments. To detect senescent endothelial cells in the aging mouse brain, we analyzed 4233 cells in fractions enriched for cerebromicrovascular endothelial cells and other cells associated with the neurovascular unit obtained from young (3-month-old) and aged (28-month-old) C57BL/6 mice. We define 13 transcriptomic cell types by deep, single-cell RNA sequencing. We match transcriptomic signatures of cellular senescence to endothelial cells identified on the basis of their gene expression profile. Our study demonstrates that with advanced aging, there is an increased ratio of senescent endothelial cells (~ 10%) in the mouse cerebral microcirculation. We propose that our single-cell RNA sequencing–based method can be adapted to study the effect of aging on senescence in various brain cell types as well as to evaluate the efficiency of various senolytic regimens in multiple tissues.

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Funding

This work was supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the National Institute of General Medical Sciences Oklahoma Shared Clinical and Translational Resources (OSCTR) (GM104938, to AY and JW) and Molecular Mechanisms and Genetics of Autoimmunity COBRE (P30-GM110766, to LG), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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Author notes

  1. Tamas Kiss, Ádám Nyúl-Tóth, Priya Balasubramanian and Stefano Tarantini contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA

    Tamas Kiss, Ádám Nyúl-Tóth, Priya Balasubramanian, Stefano Tarantini, Chetan Ahire, Jordan DelFavero, Andriy Yabluchanskiy, Tamas Csipo, Anna Csiszar & Zoltan Ungvari

  2. Department of Medical Physics and Informatics, International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary

    Tamas Kiss, Eszter Farkas, Anna Csiszar & Zoltan Ungvari

  3. Biological Research Centre, Institute of Biophysics, Szeged, Hungary

    Ádám Nyúl-Tóth

  4. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Stefano Tarantini, Tamas Csipo & Zoltan Ungvari

  5. Department of Public Health, International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary

    Stefano Tarantini, Andriy Yabluchanskiy & Zoltan Ungvari

  6. Department of Cardiology, International Training Program in Geroscience, Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Tamas Csipo

  7. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Graham Wiley & Lori Garman

  8. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Anna Csiszar & Zoltan Ungvari

Authors
  1. Tamas Kiss
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  2. Ádám Nyúl-Tóth
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  3. Priya Balasubramanian
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  4. Stefano Tarantini
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  5. Chetan Ahire
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  6. Jordan DelFavero
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  7. Andriy Yabluchanskiy
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  8. Tamas Csipo
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  9. Eszter Farkas
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  10. Graham Wiley
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  11. Lori Garman
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  12. Anna Csiszar
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  13. Zoltan Ungvari
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Corresponding author

Correspondence to Anna Csiszar.

Ethics declarations

All procedures were approved by the Institutional Animal Use and Care Committees of the University of Oklahoma Health Sciences Center. All animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978).

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Kiss, T., Nyúl-Tóth, Á., Balasubramanian, P. et al. Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. GeroScience 42, 429–444 (2020). https://doi.org/10.1007/s11357-020-00177-1

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  • DOI: https://doi.org/10.1007/s11357-020-00177-1

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