ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response
- Baylor College of Medicine, United States
- University of Michigan, United States
- Kanazawa Medical University, Japan
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.
Data availability
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RNA-Seq of hematopoietic stem cells from vehicle and estrogen-treated micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE99120).
Article and author information
Author details
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).
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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ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response
eLife 7:e31159.
https://doi.org/10.7554/eLife.31159
Further reading
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- Developmental Biology
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Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.
