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
-
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.
Metrics
-
- 2,480
- views
-
- 439
- downloads
-
- 40
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response
eLife 7:e31159.
https://doi.org/10.7554/eLife.31159
Further reading
-
- Stem Cells and Regenerative Medicine
The lateral wall of the mouse subventricular zone harbors neural stem cells (NSC, B cells) which generate proliferating transient-amplifying progenitors (TAP, C cells) that ultimately give rise to neuroblasts (NB, A cells). Molecular profiling at the single-cell level struggles to distinguish these different cell types. Here, we combined transcriptome analyses of FACS-sorted cells and single-cell RNAseq to demonstrate the existence of an abundant, clonogenic and multipotent population of immature neuroblasts (iNB cells) at the transition between TAP and migrating NB (mNB). iNB are reversibly engaged in neuronal differentiation. Indeed, they keep molecular features of both undifferentiated progenitors, plasticity and unexpected regenerative properties. Strikingly, they undergo important progressive molecular switches, including changes in the expression of splicing regulators leading to their differentiation in mNB subdividing them into two subtypes, iNB1 and iNB2. Due to their plastic properties, iNB could represent a new target for regenerative therapy of brain damage.
-
- Biochemistry and Chemical Biology
- Stem Cells and Regenerative Medicine
Human induced pluripotent stem cells (hiPSCs) have great potential to be used as alternatives to embryonic stem cells (hESCs) in regenerative medicine and disease modelling. In this study, we characterise the proteomes of multiple hiPSC and hESC lines derived from independent donors and find that while they express a near-identical set of proteins, they show consistent quantitative differences in the abundance of a subset of proteins. hiPSCs have increased total protein content, while maintaining a comparable cell cycle profile to hESCs, with increased abundance of cytoplasmic and mitochondrial proteins required to sustain high growth rates, including nutrient transporters and metabolic proteins. Prominent changes detected in proteins involved in mitochondrial metabolism correlated with enhanced mitochondrial potential, shown using high-resolution respirometry. hiPSCs also produced higher levels of secreted proteins, including growth factors and proteins involved in the inhibition of the immune system. The data indicate that reprogramming of fibroblasts to hiPSCs produces important differences in cytoplasmic and mitochondrial proteins compared to hESCs, with consequences affecting growth and metabolism. This study improves our understanding of the molecular differences between hiPSCs and hESCs, with implications for potential risks and benefits for their use in future disease modelling and therapeutic applications.
