An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.

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Highlights d Mitochondrial heterogeneity reveals fundamental metabolic properties of HSCs d Lysosomal repression enhances HSC quiescence and potency d Active, but not quiescent, HSCs use glycolysis as their main source of energy d Label-retaining dormant HSCs and low-MMP HSCs exhibit overlapping molecular signatures

SummaryAging hematopoietic stem cells (HSCs) exhibit defective lineage specification that is thought to be central to increased incidence of myeloid malignancies and compromised immune competence in the elderly. Mechanisms underlying these age-related defects remain largely unknown. We show that the deacetylase Sirtuin (SIRT)1 is required for homeostatic HSC maintenance. Differentiation of young SIRT1-deleted HSCs is skewed toward myeloid lineage associated with a significant decline in the lymphoid compartment, anemia, and altered expression of associated genes. Combined with HSC accumulation of damaged DNA and expression patterns of age-linked molecules, these have striking overlaps with aged HSCs. We further show that SIRT1 controls HSC homeostasis via the longevity transcription factor FOXO3. These findings suggest that SIRT1 is essential for HSC homeostasis and lineage specification. They also indicate that SIRT1 might contribute to delaying HSC aging.

Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3 À/À HSC that are defective in their activity. We show that Foxo3 À/À HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3 À/À hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3 À/À HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells.