Brain endothelial cells are exquisite sensors of age-related circulatory cues

Abstract

Highlights 19• Single-cell RNA sequencing of brain endothelial cells (BECs) reveals transcriptional 20 segmentation into distinct arterial, capillary, and venous identities with age and 21 experimental interventions 22 • Changes with age are heterogenous across vessel segments, with aged capillaries 23 enriched in signatures of innate immunity, TGF-b and VEGF signaling, hypoxia and 24 oxidative stress 25 • BECs sense and respond transcriptionally to diverse circulatory cues: inflammatory, pro-26 aging, or rejuvenating 27 • Aged plasma exposure recapitulates-and young plasma reverses-key transcriptomic 28 signatures of normal BEC aging 29 • BEC response to aged and young plasma reveals cell non-autonomous mechanisms of 30 blood-brain-barrier aging SUMMARY 33Brain endothelial cells (BECs) are key elements of the blood-brain barrier (BBB), protecting the 34 brain from pathogens and restricting access to circulatory factors. Recent studies have 35 demonstrated that the circulatory environment can modulate brain aging, yet, the underlying 36 processes remain largely unknown. Given the BBB's intermediary position, we hypothesized that 37 BECs sense, adapt to, and relay signals between the aging blood and brain. We sequenced single 38 endothelial cells from the hippocampus-a brain region key to learning, memory, and 39 neurogenesis-of healthy young and aged mice as well as post-exposure to inflammatory and 40 age-related circulatory factors. We discovered that aged capillary BECs, compared with arterial 41 and venous cells, exhibit the greatest transcriptional changes, upregulating innate immunity, 42 antigen presentation, TGF-b signaling and oxidative stress response pathways. Remarkably, 43 short-term infusions of aged plasma into young mice recapitulated key aspects of this aging 44 transcriptome, while infusions of young plasma into aged mice reversed select aging signatures, 45 essentially rejuvenating the BBB endothelium transcriptome. We identify candidate pathways 46 mediating blood-borne brain rejuvenation by comparing age-upregulated genes with those 47 modulated by plasma exposure. Together, these findings suggest that the transcriptional age of 48 BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a 49 promising therapeutic target to treat brain disease. 50 51

Dach1 extends artery networks and protects against cardiac injury

“…3C). This is consistent with previous analyses showing that brain and heart capillary ECs exist along a continuum of arterial-venous identity, even in adults (Chen et al, 2020;Su et al, 2018;Vanlandewijck et al, 2018). Nonetheless, cells from all clusters were found in both genotypes (Fig.…”

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

“…The practical pharmacological approach we demonstrated complements the recent exciting discovery that young plasma infusion can partially reverse ageing-associated EC transcriptomic alterations 76 . In fact, apart from the reversal of expression changes in the aged brain endothelium, GLP-1R agonist treatment and young plasma infusion appear to share several functional benefits in animal models, such as amelioration of neuroinflammation 32,77 , rescuing synaptic plasticity deficits and cognitive benefits in aged or AD mouse 78,79 .…”

Secondary single-cell transcriptomic analysis reveals common molecular signatures of cerebrovascular injury between traumatic brain injury and aging

“…Interestingly, a transmembrane protein, Tmem252, with unknown function is highly and specifically expressed in EC under mTBI condition and aging process but almost absent in normal condition. Coincidentally, Tmem252 is also dramatically upregulated in stroke (Zeng et al, 2019) and LPS-induced vascular inflammation (Chen et al, 2020), suggesting that Tmem252 may be a common regulator of cerebrovascular injury. PC dysfunction has been reported in many pathologic conditions, such as mTBI, stroke, and AD (Sweeney et al, 2018).…”