FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging.
Stress or aging of tissue-specific stem cells is considered central to the decline of tissue homeostasis in the elderly, although little is known of molecular mechanisms underlying hematopoietic stem cell (HSC) aging and stress resistance. Here, we report that mice lacking the transcription factor forkhead box O3a (FoxO3a) develop neutrophilia associated with inhibition of the up-regulation of negative regulator of cell proliferation, Sprouty-related Ena/VASP homology 1 domain-containing proteins 2 (Spred2) and AKT and ERK activation, in HSCs during hematopoietic recovery following myelosuppressive stress conditions. Compared with aged wild-type mice, more severe neutrophilia was also observed in aged Foxo3a-deficient mice. AKT and ERK activation and inhibition of Spred2 were detected in HSCs from aged FoxO3a-deficient mice. Spred2-deficient mice also developed neutrophilia during hematopoietic recovery following myelosuppressive stress, indicating that FoxO3a plays a pivotal role in maintenance, integrity, and stress resistance of HSCs through negative feedback pathways for proliferation. This will provide new insight into the hematopoietic homeostasis in conditions of aging and stress.
Miyamoto
Kana
K
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine,Shinano-machi, Tokyo, Japan. miyamoto@sc.itc.keio.ac.jp
Miyamoto
Takeshi
T
Kato
Reiko
R
Yoshimura
Akihiko
A
Motoyama
Noboru
N
Suda
Toshio
T
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics / Q000502:physiology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009503:Neutropenia / Q000235:genetics / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases
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