Endothelial mTOR maintains hematopoiesis during aging.
Endothelial mTOR maintains hematopoiesis during aging.
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DOI：
10.1084/jem.20191212
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发表时间：
2020-06-01
期刊：
影响因子：
--
通讯作者：
Butler JM
中科院分区：
文献类型：
--
作者：
Ramalingam P;Poulos MG;Gutkin MC;Katsnelson L;Freire AG;Lazzari E;Butler JM
Ramalingam等人证明，mTOR的药理学抑制对衰老的造血有不利影响。作者证明，衰老导致骨髓内皮细胞内mTOR信号传导减少，并且mTOR的内皮特异性抑制导致在生理衰老期间观察到的造血缺陷。衰老导致造血干细胞和祖细胞（HSPC）功能下降。我们最近发现，骨髓内皮细胞（BMEC）的老化导致BMEC小生境和HSPC之间的串扰改变，这指示年轻的HSPC表现为老年HSPC。在这里，我们证明了衰老导致BMEC内mTOR信号转导的减少，这可能是其生态位活性的年龄相关损伤的基础。我们的研究结果表明，使用雷帕霉素的mTOR的药理学抑制对造血具有有害影响。为了正式确定mTOR的内皮特异性抑制是否可以影响造血老化，我们有条件地删除了年轻小鼠EC中的mTOR（mTOR（ECKO）），并观察到它们的HSPC显示出老化造血系统的属性。来自mTOR（ECKO）小鼠的HSPC的转录谱显示它们的转录组类似于老化的HSPC。值得注意的是，在连续移植期间，野生型HSPC暴露于mTOR（ECKO）微环境足以概括衰老相关的表型，证实了EC来源的信号在控制HSPC衰老中的指导作用。
Ramalingam et al. demonstrate that pharmacological inhibition of mTOR adversely impacts aging hematopoiesis. The authors demonstrate that aging results in decreased mTOR signaling within the bone marrow endothelium and endothelial-specific inhibition of mTOR causes hematopoietic defects observed during physiological aging. 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.
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影响因子：
23.9
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