FOXO3A directs a protective autophagy program in haematopoietic stem cells

摘要

Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-drivenpro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.%用小鼠所做的这项研究表明，在动物生中，生成成熟血细胞的自更新造血干细胞(HSCs)通过由自吞噬作用介导的生存反应得到保护，使其不受代谢应激的影响，而这种反应则是由转录因子FOXCO3A的表达触发的。因此，在通过保护成年HSCs来帮助维持血液平衡的同时，自吞噬作用还可能通过允许受损伤的、丧失功能的或被改变的老HSCs(它们是与年龄相关的血液病发病中的关键冈素)存活而对血液系统的衰老间接做出贡献。