Heritable ER stress impairs mitochondrial metabolism and leads to exhaustion of low-dose irradiated hematopoietic stem cells [RREMseqHSC]

How hematopoietic stem cells (HSC) respond to low levels of stress such as exposure to very low doses of radiation currently used in medicine, is largely unknown. Here, we show that 20mGy-irradiated HSC (20mGy-HSC) exhibit, when they proliferate, oxidative stress with increased mitochondrial Reactive Oxygen Species and metabolism together with mitochondrial Ca2+ overload. These mitochondrial defects are due to an immediate and sustained endoplasmic reticulum (ER) stress adapted by proliferative 20mGy-HSC through activation of the eIF2?-ATF4 branch of the UPR. The ER stress is heritable and leads, in long-term quiescent 20mGy-HSC, to activation of the IRE1?-Xbp1 branch of UPR, which fails to restore ER homeostasis resulting in HSC self-renewal deficiency and exhaustion. Finally, we show that this heritable ER stress leads to a global DNA hypomethylation, partially reverted by early inhibition of ER stress. Our studies illuminate how an adaptive ER stress response can lead to mitochondrial defects and HSC deficiency. Overall design: DNA methylation profiling in HSC isolated from bone marrow of mice transplanted with sham or 20mGy-irradiated LSK, pre-treated or not with 4PBA