Brain Endothelial Cells Are Exquisite Sensors of Age-Related Circulatory Cues

• Published in: Cell reports (Cambridge) Vol. 30; no. 13; pp. 4418 - 4432.e4
• Main Authors: Chen, Michelle B., Yang, Andrew C., Yousef, Hanadie, Lee, Davis, Chen, Winnie, Schaum, Nicholas, Lehallier, Benoit, Quake, Stephen R., Wyss-Coray, Tony
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.03.2020
• Subjects: aging; Aging - blood; Aging - genetics; Aging - physiology; Animals; Arteries - physiology; Blood Circulation - physiology; blood-brain barrier; Brain - cytology; brain endothelial cells; Capillaries - physiology; Endothelial Cells - metabolism; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - pharmacology; Male; Mice, Inbred C57BL; plasma proteome; rejuvenation; single-cell RNA sequencing; Transcription, Genetic - drug effects; Transcriptome - genetics; Veins - physiology; blood-brain barrier; single-cell RNA sequencing; brain endothelial cells; aging; rejuvenation; plasma proteome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.03.012

Brain endothelial cells (BECs) are key constituents of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Yet, because circulatory proteins have prominent age-related effects on adult neurogenesis, neuroinflammation, and cognitive function in mice, we wondered whether BECs receive and potentially relay signals between the blood and brain. Using single-cell RNA sequencing of hippocampal BECs, we discover that capillary BECs—compared with arterial and venous BECs—undergo the greatest transcriptional changes in normal aging, upregulating innate immunity and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulate key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice exert rejuvenation effects on the capillary transcriptome. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease. [Display omitted] •Brain capillary, arterial, and venous cells age differently at the transcriptome level•Aged capillaries upregulate innate immunity and oxidative stress pathways•Capillary transcriptomes respond to inflammatory and age-related circulatory cues•Aged and young plasma mimics and reverses signatures of normal aging, respectively Through scRNA-seq, Chen et al. demonstrate how mouse hippocampal capillary cells undergo significant alterations with age, including the upregulation of innate immunity and oxidative stress pathways, and that components of these aging signatures can be recapitulated or rejuvenated with acute exposure to aged or young mouse plasma, respectively.