Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells

Abstract

Unchecked accumulation of reactive oxygen species (ROS) compromises maintenance of hematopoietic stem cells. Regulation of ROS by the tumor suppressor protein ataxia telangiectasia mutated (ATM) is critical for preserving the hematopoietic stem cell pool. In this study we demonstrate that the Foxo3 member of the Forkhead Box O (FoxO) family of transcription factors is essential for normal ATM expression. In addition, we show that loss of Foxo3 leads to defects in hematopoietic stem cells, and these defects result from an overaccumulation of ROS. Foxo3 suppression of ROS in hematopoietic stem cells is mediated partly by regulation of ATM expression. We identify ROSindependent modulations of ATM and p16INK4a and ROSmediated activation of p53/p21 CIP1/WAF1/Sdi1 tumor suppressor pathways as major contributors to Foxo3-null hematopoietic stem cells defects. Our studies demonstrate that Foxo3 represses ROS in part via regulation of ATM and that this repression is required for maintenance of the hematopoietic stem cell pool.

Mechanisms of self-renewal in hematopoietic stem cells

“…FoxO3a-deficient HSCs showed more severe reduction in repopulating capacity upon aging [113]. Another research group reported a similar finding, suggesting that Foxo3 is the main player of the FoxO family in HSCs [114]. Warr et al focused on cell autophagy in HSCs.…”

Epigenetic regulation of aging stem cells

“…In adult HSCs and NSCs, FOXO factors cooperate to regulate stem cell selfrenewal and homeostasis. Conditional deletion of FoxO1, FoxO3 and FoxO4 in the adult hematopoietic system, as well as germline deletion of the single FoxO3 gene, trigger a loss in long-term repopulating capacity of HSCs due to enhanced exit from quiescence, increased apoptosis and increased levels of reactive oxygen species (Miyamoto et al, 2007;Tothova and Gilliland 2007;Yalcin et al, 2008). FOXO transcription factors are also necessary for the maintenance of adult NSCs (Paik et al, 2009;Renault et al, 2009).…”

Hematopoietic Stem Cell Injury Induced by Ionizing Radiation

“…The mechanism by which IR induces HSC senescence remains to be elucidated but may be attributable to increased production of ROS because a large body of evidence suggests that ROS plays an important role in mediating the induction of HSC senescence under various pathological conditions (69,112,127,149,167). For example, it was found that ATM -/ -mice exhibit progressive failure of hematopoietic function with aging (69).…”

“…Treatment of FoxOs knockout mice with NAC reversed the defects of HSCs and hematopoietic abnormalities. It appears that FoxO3 is the primary regulator of HSCs because the deletion of FoxO3 alone in mice can recapitulate most of the phenotypes observed in the tripleFoxO knockout mice (112,167). The molecular basis for FoxOs to regulate ROS production in HSCs is mainly attributed to their transcriptional regulation of the expression of superoxide dismutase and catalase (149).…”