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

Chen, Michelle B.; Yang, Andrew; Yousef, Hanadie; Lee, Davis; Chen, Winnie; Schaum, Nicholas; Lehallier, Benoit; Quake, Stephen R.; Wyss‐Coray, Tony

doi:10.1016/j.celrep.2020.03.012

Cited by 159 publications

(145 citation statements)

References 88 publications

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“…These could potentially accelerate, delay or even reverse the rate of aging of other tissues in the body. Indeed, scRNA-seq studies of brain endothelial cell aging showed that infusion of aged plasma can accelerate while young plasma can reverse aging as determined by analysis of the transcriptome 70 . These studies highlight the fact that cellular aging does not occur independent of influences that are both local and systemic.…”

Section: Is Aging Contagious?mentioning

confidence: 99%

Asynchronous, contagious and digital aging

Rando

Wyss‐Coray

2021

Nat Aging

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Section: Is Aging Contagious?mentioning

confidence: 99%

Asynchronous, contagious and digital aging

Rando

Wyss‐Coray

2021

Nat Aging

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“…With 80-2,432 DEGs each due to young or aged blood, ECs across all tissues seem susceptible to blood-borne influences, albeit with tissue-specificity, perhaps due to differences in perfusion, differences in cell intrinsic programs, or influence from parenchymal cells. Recently, transfused aged plasma was shown to recapitulate transcriptomic ageing of hippocampal ECs, and young plasma reversed aspects of ageing, especially in capillary ECs 12 .…”

Section: Cell Type-specific Differential Gene Expressionmentioning

confidence: 99%

“…Notably, such signatures are absent in certain cell types (Extended Data Fig. 6), including brain endothelial cells (BECs), which have been observed to undergo increased expression of electron transport chain genes with age 12 . This effect is replicated by exposure to aged mouse plasma, and reversed by exposure to young mouse plasma in vivo 12 .…”

Section: Young Blood Reverses Mitochondrial and Global Gene Expression mentioning

confidence: 99%

Molecular hallmarks of heterochronic parabiosis at single cell resolution

Pálovics¹,

Keller

Schaum³

et al. 2020

Preprint

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Slowing or reversing biological ageing would have major implications for mitigating disease risk and maintaining vitality. While an increasing number of interventions show promise for rejuvenation, the effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. We performed single-cell RNA-sequencing on 13 organs to reveal cell type specific responses to young or aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, hematopoietic stem cells, hepatocytes, and endothelial cells from multiple tissues appear especially responsive. On the pathway level, young blood invokes novel gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. Intriguingly, we observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it. Altogether, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

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“…It should be noted that although our ndings suggest that reduction of pericyte coverage leads to BBB dysfunction through increased endothelial transcytosis following CCH, we cannot answer the question that why EC, directly links the blood and neural function, is not the primary cause of BBB dysfunction [50].…”

Section: Ec Acts As An Important Component Of Direct Communication Bementioning

confidence: 61%

Reduction of Pericyte Coverage Leads to Blood-Brain Barrier Dysfunction Via Endothelial Transcytosis Following Chronic Cerebral Hypoperfusion

Sun

Gao

et al. 2021

Preprint

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Background: Chronic cerebral hypoperfusion (CCH) is the leading cause for cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WML) in CSVD. But the effects of CCH on BBB integrity and constituents as well as the cellular and molecular mechanisms about the consequences of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH induced brain damage has also not been explored. Methods: In this study, we used a rat model of CSVD, established via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB was assessed using immunostaining, western blotting and transmission electron microscopy. Data were analyzed using the one-way ANOVA test or two-tailed unpaired Student’s t tests.Results: We noted a transient yet severe breakdown of the BBB in the CC following CCH. The BBB was severely impaired as early as 1 day post operation and most severely impaired 3 days post operation. BBB breakdown preceded WML and neuroinflammatory responses. Moreover, pericyte loss was associated with BBB impairment and accumulation of serum proteins was mediated by increased endothelial transcytosis in the CC. BBB dysfunction led to brain damage by regulating TGF-β/Smad2 signaling. Further, protection of the BBB via inhibition of endothelial transcytosis ameliorated serum proteins leakage, microglial activation, oligodendrocyte progenitor cells (OPCs) activation and inappropriate TGF-β/Smad2 signaling activation. Conclusions: Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis and protection of the BBB integrity ameliorates brain damage by regulating TGF-β/Smad2 signaling following CCH, therefore reversal of BBB dysfunction may be a promising strategy to treat CSVD.

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

Cited by 159 publications

References 88 publications

Asynchronous, contagious and digital aging

Asynchronous, contagious and digital aging

Molecular hallmarks of heterochronic parabiosis at single cell resolution

Reduction of Pericyte Coverage Leads to Blood-Brain Barrier Dysfunction Via Endothelial Transcytosis Following Chronic Cerebral Hypoperfusion

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