Department of Bioengineering, Stanford University, Stanford, CA, USA.
Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
Cell Rep. 2020 Mar 31;30(13):4418-4432.e4. 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.
脑内皮细胞（BEC）是血脑屏障（BBB）的重要组成部分，可保护大脑免受病原体侵害，并限制循环因子进入大脑。然而，由于循环蛋白对成年神经发生、神经炎症和认知功能具有明显的与年龄相关的影响，我们想知道 BEC 是否接收并可能在血液和大脑之间传递信号。通过对海马 BEC 的单细胞 RNA 测序，我们发现与动脉和静脉 BEC 相比，毛细血管 BEC 在正常衰老过程中经历了最大的转录变化，上调了先天免疫和氧化应激反应途径。将衰老的血浆短期输注到年轻小鼠体内，重现了这种衰老转录组的关键方面，令人惊讶的是，将年轻的血浆输注到老年小鼠体内，对毛细血管转录组产生了年轻化效应。这些发现表明，BEC 的转录年龄对与年龄相关的循环线索非常敏感，并指出 BBB 本身是治疗脑部疾病的一个很有前途的治疗靶点。
