1. Stem Cells and Regenerative Medicine
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ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response

  1. Richard H Chapple
  2. Tianyuan Hu
  3. Yu-Jung Tseng
  4. Lu Liu
  5. Ayumi Kitano
  6. Victor Luu
  7. Kevin A Hoegenauer
  8. Takao Iwawaki
  9. Qing Li
  10. Daisuke Nakada  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. University of Michigan, United States
  3. Kanazawa Medical University, Japan
Research Article
  • Cited 27
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Cite this article as: eLife 2018;7:e31159 doi: 10.7554/eLife.31159

Abstract

Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation. We found that estrogen signals through estrogen receptor α (ERα) expressed in hematopoietic cells to activate the protective Ire1α-Xbp1 branch of the UPR. Further, ERα-mediated activation of the Ire1α-Xbp1 pathway confers HSCs with resistance against proteotoxic stress and promotes regeneration. Our findings reveal a systemic mechanism through which HSC function is augmented for hematopoietic regeneration.

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Author details

  1. Richard H Chapple

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tianyuan Hu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu-Jung Tseng

    Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lu Liu

    Department of Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ayumi Kitano

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Victor Luu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kevin A Hoegenauer

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Takao Iwawaki

    Department of Life Sciences, Kanazawa Medical University, Kahoku, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Qing Li

    Department of Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Daisuke Nakada

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    nakada@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6010-7094

Funding

National Cancer Institute (CA193235)

  • Daisuke Nakada

National Heart, Lung, and Blood Institute (HL132392)

  • Qing Li

National Institute of Diabetes and Digestive and Kidney Diseases (DK107413)

  • Daisuke Nakada

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mice were housed in AAALAC-accredited, specific-pathogen-free animal care facilities at Baylor College of Medicine (BCM), or University of Michigan (UM) with 12hr light-dark cycle and received standard chow ad libitum. All procedures were approved by the BCM or UM Institutional Animal Care and Use Committees (protocol #AN-5858).

Reviewing Editor

  1. Cristina Lo Celso, Imperial College London, United Kingdom

Publication history

  1. Received: August 10, 2017
  2. Accepted: February 15, 2018
  3. Accepted Manuscript published: February 16, 2018 (version 1)
  4. Version of Record published: February 28, 2018 (version 2)

Copyright

© 2018, Chapple et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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