FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.
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.
Tothova
Zuzana
Z
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Kollipara
Ramya
R
Huntly
Brian J
BJ
Lee
Benjamin H
BH
Castrillon
Diego H
DH
Cullen
Dana E
DE
McDowell
Elizabeth P
EP
Lazo-Kallanian
Suzan
S
Williams
Ifor R
IR
Sears
Christopher
C
Armstrong
Scott A
SA
Passegué
Emmanuelle
E
DePinho
Ronald A
RA
Gilliland
D Gary
DG
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D000975:Antioxidants; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors