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Nrf2 regulates haematopoietic stem cell function

Nature Cell Biology volume 15, pages 309–316 (2013)Cite this article

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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 microenvironment1. 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.

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Figure 1: Nrf2−/− mice exhibit an expanded haematopoietic stem and progenitor pool.
Figure 2: Nrf2 regulates HSPC proliferation and differentiation intrinsically.
Figure 3: Nrf2 maintains HSC quiescence and self-renewal.
Figure 4: Nrf2 governs HSPC retention and migration to the bone marrow niche.
Figure 5: Nrf2 mediates HSPC functions through CXCR4.

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Acknowledgements

We thank J. Chan (University of California, Irvine, USA) for providing the Nrf2−/− mice; the staff of the Memorial Sloan-Kettering Cancer Center Research Animal Resources Center for excellent animal care; and the staff of the Flow Cytometry Core Facility and M. S. Jiao of the Comparative Pathology Laboratories for assistance with sample preparation. This research was supported by National Institutes of Health award numbers RO1-HL069929 (M.R.M.v.d.B.), R01-AI100288 (M.R.M.v.d.B.), R01-AI080455 (M.R.M.v.d.B.), R01-AI101406 (M.R.M.v.d.B.) and P01-CA023766 (ROR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was also received from the Radiation Effects Research Foundation (RERF-NIAID; M.R.M.v.d.B.), The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by W. H. Goodwin and A. Goodwin, The Lymphoma Foundation, Alex’s Lemonade Stand, The Geoffrey Beene Cancer Research Center at Memorial Sloan-Kettering Cancer Center, and The Peter Solomon Fund. J.A.D. was supported by an Australian National Health and Medical Research Council Biomedical Training Fellowship and a Research Fellowship from the Leukemia and Lymphoma Society. E.V. was supported by a fellowship from the Italian Foundation for Cancer Research.

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Authors and Affiliations

  1. Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    Jennifer J. Tsai, Jarrod A. Dudakov, Koichi Takahashi, Enrico Velardi, Amanda M. Holland, Natalie V. Singer, Mallory L. West, Odette M. Smith, Lauren F. Young, Yusuke Shono, Arnab Ghosh, Alan M. Hanash, Hien T. Tran & Marcel R. M. van den Brink

  2. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    Jennifer J. Tsai, Jarrod A. Dudakov, Koichi Takahashi, Enrico Velardi, Amanda M. Holland, Natalie V. Singer, Mallory L. West, Odette M. Smith, Lauren F. Young, Yusuke Shono, Arnab Ghosh, Alan M. Hanash, Hien T. Tran & Marcel R. M. van den Brink

  3. Department of Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA

    Jennifer J. Tsai & Amanda M. Holland

  4. Monash Immunology and Stem Cell Laboratories, Monash University, Clayton 3800, Australia

    Jarrod A. Dudakov

  5. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    Jae-Hung Shieh & Malcolm A. S. Moore

  6. Department of Clinical and Experimental Medicine, University of Perugia, 06122 Perugia, Italy

    Enrico Velardi

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Contributions

J.J.T. designed and performed the experiments. J.A.D., K.T., J.S. and E.V. assisted with experiments and provided substantial intellectual inputs. N.V.S., M.L.W., O.M.S. and L.F.Y. assisted with experiments. A. M. Holland, A. M. Hanash, A.G. and H.H.T. provided intellectual inputs. M.A.S.M. and M.R.M.v.d.B. guided the research. J.J.T., J.A.D., K.T., A. M. Holland, Y.S. and M.R.M.v.d.B. wrote the manuscript.

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Correspondence to Marcel R. M. van den Brink.

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The authors declare no competing financial interests.

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Tsai, J., Dudakov, J., Takahashi, K. et al. Nrf2 regulates haematopoietic stem cell function. Nat Cell Biol 15, 309–316 (2013). https://doi.org/10.1038/ncb2699

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