FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.

By Z. Tothova, R. Kollipara, B. Huntly, Benjamin H. Lee, D. Castrillon, Dana E. Cullen, Elizabeth Mcdowell, S. Lazo-Kallanian, Ifor R. Williams, C. Sears and 4 more. Cell, 2007

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To understand the role of FoxO family members in hematopoiesis, we conditionally deleted FoxO1, FoxO3, and FoxO4 in the adult hematopoietic system. FoxO-deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative Sca-1+, c-Kit+ (LSK) compartment that contains the short- and long-term hematopoietic stem cell (HSC) populations. FoxO-deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSC. Notably, there was a marked context-dependent increase in reactive oxygen species (ROS) in FoxO-deficient HSC compared with wild-type HSC that correlated with changes in expression of genes that regulate ROS. Furthermore, in vivo treatment with the antioxidative agent N-acetyl-L-cysteine resulted in reversion of the FoxO-deficient HSC phenotype. Thus, FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential.

Subfields: Hematology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/244cd8170eb178f5fc628481296235650b14e656

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Citations in the corpus

Oxidative Stress, Mitochondrial Dysfunction, and Aging (2011, background): “AD is characterized by severe neurodegenerative changes, such as cerebral atrophy, loss of neurons and synapses, and selective depletion of neurotransmitter systems in cerebral cortex and certain subcortical region [167].”
Reactive oxygen species in cancer (2010, background): “Also increased was the expression of FOXO1, a forkhead transcription factor that was previously implicated in the regulation of other ROS scavengers such as SOD and catalase to confer resistance to oxidative stress in hematopoietic stem cells [223].”
Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation (2008, background): “Although individual Foxo knockouts had no haematopoietic phenotype, an inducible triple knockout animal — Foxo1 / 3 / 4 flox/flox in Mx1 -Cre mice (Cre recombinase under the control of the interferon-inducible Mx1 promoter) — did reveal haematopoietic defect”
Signal transduction by reactive oxygen species (2011, background): “HSCs lacking FoxO1, FoxO3, and FoxO4 had reduced expression of antioxidant proteins such as superoxide dismutase and catalase and corresponding increase in ROS levels within the HSC compartment (Tothova et al., 2007).”
Stems cells and the pathways to aging and cancer. (2008, background): “In another study, HSCs from mice lacking Foxo transcription factors (Foxo1/Foxo3/Foxo4 triple mutants) showed enhanced short-term yet diminished long-term repopulation activity associated with increased cycling, apoptosis, and reduced stem and progenitor cell reserves (Tothova et al., 2007).”
The Oxygen Rich Postnatal Environment Induces Cardiomyocyte Cell Cycle Arrest Through DNA Damage Response (2014, neutral): “can be proproliferative in several scenarios (Leslie, 2006; Tothova et al., 2007) and can stimulate differentiation of several cell types (Lee et al.”
ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis (2007, background): “This FOXO ROS-protective function is important for stem-cell surviva”