FOXO3A directs a protective autophagy program in haematopoietic stem cells

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-driven pro-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. Autophagy is shown to be an essential mechanism that protects haematopoietic stem cells from metabolic stress; the transcription factor FOXO3A maintains a pro-autophagy gene expression program that poises haematopoietic stem cells to rapidly mount a protective autophagic response upon metabolic stress. This study in mice shows that the self-renewing haematopoietic stem cells (HSCs) that give rise to mature blood cells throughout life are protected from metabolic stress by an autophagy-mediated survival response triggered by the expression of the transcription factor FOXO3A. Thus at the same time as helping to maintain blood homeostasis by protecting adult HSCs, autophagy may indirectly contribute to the ageing of the blood system by allowing the survival of damaged, dysfunctional or transformed old HSCs, which are key actors in the development of age-related blood disorders.