Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medical College, New York, NY.
Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ.
J Exp Med. 2020 Jun 1;217(6). doi: 10.1084/jem.20191212.
Aging leads to a decline in hematopoietic stem and progenitor cell (HSPC) function. We recently discovered that aging of bone marrow endothelial cells (BMECs) leads to an altered crosstalk between the BMEC niche and HSPCs, which instructs young HSPCs to behave as aged HSPCs. Here, we demonstrate aging leads to a decrease in mTOR signaling within BMECs that potentially underlies the age-related impairment of their niche activity. Our findings reveal that pharmacological inhibition of mTOR using Rapamycin has deleterious effects on hematopoiesis. To formally determine whether endothelial-specific inhibition of mTOR can influence hematopoietic aging, we conditionally deleted mTOR in ECs (mTOR(ECKO)) of young mice and observed that their HSPCs displayed attributes of an aged hematopoietic system. Transcriptional profiling of HSPCs from mTOR(ECKO) mice revealed that their transcriptome resembled aged HSPCs. Notably, during serial transplantations, exposure of wild-type HSPCs to an mTOR(ECKO) microenvironment was sufficient to recapitulate aging-associated phenotypes, confirming the instructive role of EC-derived signals in governing HSPC aging.
衰老是导致造血干细胞和祖细胞 (HSPC) 功能下降的原因。我们最近发现，骨髓内皮细胞 (BMEC) 的衰老会导致 BMEC 龛位与 HSPC 之间的交流发生改变，从而指示年轻的 HSPC 表现得像衰老的 HSPC 一样。在这里，我们证明衰老会导致 BMEC 内 mTOR 信号的减少，这可能是其龛位活性与年龄相关的损伤的基础。我们的发现表明，使用雷帕霉素抑制 mTOR 的药理作用对造血有不良影响。为了正式确定内皮细胞特异性抑制 mTOR 是否会影响造血衰老，我们在年轻小鼠的 ECs (mTOR(ECKO)) 中条件性地删除 mTOR，并观察到它们的 HSPC 表现出衰老造血系统的特征。mTOR(ECKO) 小鼠 HSPC 的转录组分析表明，它们的转录组与衰老的 HSPC 相似。值得注意的是，在连续移植过程中，将野生型 HSPC 暴露于 mTOR(ECKO) 微环境中足以再现与衰老相关的表型，这证实了 EC 衍生信号在调节 HSPC 衰老中的指导作用。
