1. Nrf2 regulates haematopoietic stem cell function
- Author
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Jennifer Tsai, Koichi Takahashi, Alan M. Hanash, Marcel R.M. van den Brink, Malcolm A.S. Moore, Amanda M. Holland, Arnab Ghosh, Mallory L. West, Jae-Hung Shieh, Odette M. Smith, Enrico Velardi, Jarrod A Dudakov, Hien Tran, Yusuke Shono, Natalie V. Singer, and Lauren Florence Young
- Subjects
Chromatin Immunoprecipitation ,Receptors, CXCR4 ,Cell signaling ,Stromal cell ,NF-E2-Related Factor 2 ,Blotting, Western ,Regulator ,Cell Communication ,Biology ,Real-Time Polymerase Chain Reaction ,Transfection ,CXCR4 ,Article ,Mice ,Bone Marrow ,Animals ,RNA, Messenger ,Progenitor cell ,Luciferases ,Bone Marrow Transplantation ,Cell Proliferation ,Mice, Knockout ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Biology ,Flow Cytometry ,Hematopoietic Stem Cells ,Hematopoiesis ,Cell biology ,Haematopoiesis ,Female ,Stromal Cells ,Stem cell ,Signal transduction ,Signal Transduction - 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.
- Published
- 2013
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