title: Nrf2 regulates haematopoietic stem cell function.
abstract: Coordinating the balance between haematopoietic stem cell (HSC) quiescence and self-renewal is crucial for maintaining haematopoiesis lifelong. Equally important for haematopoietic function is modulating HSC localization within the bone marrow niches, as maintenance of HSC function is tightly controlled by a complex network of intrinsic molecular mechanisms and extrinsic signalling interactions with their surrounding microenvironment. In this study we demonstrate that nuclear factor erythroid 2-related factor 2 (Nfe2l2, or Nrf2), well established as a global regulator of the oxidative stress response, plays a regulatory role in several aspects of HSC homeostasis. Nrf2 deficiency results in an expansion of the haematopoietic stem and progenitor cell compartment due to cell-intrinsic hyperproliferation, which was accomplished at the expense of HSC quiescence and self-renewal. We further show that Nrf2 modulates both migration and retention of HSCs in their niche. Moreover, we identify a previously unrecognized link between Nrf2 and CXCR4, contributing, at least partially, to the maintenance of HSC function.
authors: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Jennifer J
authors: JJ
authors: Tsai
authors: Jarrod A
authors: JA
authors: Dudakov
authors: Koichi
authors: K
authors: Takahashi
authors: Jae-Hung
authors: JH
authors: Shieh
authors: Enrico
authors: E
authors: Velardi
authors: Amanda M
authors: AM
authors: Holland
authors: Natalie V
authors: NV
authors: Singer
authors: Mallory L
authors: ML
authors: West
authors: Odette M
authors: OM
authors: Smith
authors: Lauren F
authors: LF
authors: Young
authors: Yusuke
authors: Y
authors: Shono
authors: Arnab
authors: A
authors: Ghosh
authors: Alan M
authors: AM
authors: Hanash
authors: Hien T
authors: HT
authors: Tran
authors: Malcolm A S
authors: MA
authors: Moore
authors: Marcel R M
authors: MR
authors: van den Brink
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002450:Cell Communication; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D014162:Transfection
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D008156:Luciferases