Letter | Published:

Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy

Nature volume 505, pages 555558 (23 January 2014) | Download Citation

Abstract

Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain stem cells that are directly or indirectly regulated by sex hormones1,2,3,4,5,6. An important question is whether stem cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not show sex-specific morphological differences. The terminal differentiation and function of some haematopoietic cells are regulated by sex hormones7,8,9,10, but haematopoietic stem-cell function is thought to be similar in both sexes. Here we show that mouse haematopoietic stem cells exhibit sex differences in cell-cycle regulation by oestrogen. Haematopoietic stem cells in female mice divide significantly more frequently than in male mice. This difference depends on the ovaries but not the testes. Administration of oestradiol, a hormone produced mainly in the ovaries, increased haematopoietic stem-cell division in males and females. Oestrogen levels increased during pregnancy, increasing haematopoietic stem-cell division, haematopoietic stem-cell frequency, cellularity, and erythropoiesis in the spleen. Haematopoietic stem cells expressed high levels of oestrogen receptor-α (ERα). Conditional deletion of ERα from haematopoietic stem cells reduced haematopoietic stem-cell division in female, but not male, mice and attenuated the increases in haematopoietic stem-cell division, haematopoietic stem-cell frequency, and erythropoiesis during pregnancy. Oestrogen/ERα signalling promotes haematopoietic stem-cell self-renewal, expanding splenic haematopoietic stem cells and erythropoiesis during pregnancy.

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Gene Expression Omnibus

Data deposits

Microarray data have been deposited to the Gene Expression Omnibus under accession number GSE52711.

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Acknowledgements

S.J.M. is a Howard Hughes Medical Institute Investigator and the Mary McDermott Cook Chair in Pediatric Genetics. This work was supported by the Cancer Prevention and Research Institute of Texas (awards to D.N. and S.J.M.) and the National Heart Lung and Blood Institute (HL097760 to S.J.M.). B.P.L. was supported by an Irvington Institute-Cancer Research Institute/Edmond J. Safra Memorial Fellowship. Flow-cytometry was partially supported by the National Institutes of Health (NCRR grant S10RR024574, NIAID AI036211 and NCI P30CA125123) for the BCM Cytometry and Cell Sorting Core. We also thank J. Richards, S. Mani and former members of the Nakada laboratory for discussions. This work was initiated in the Life Sciences Institute at the University of Michigan then completed at Baylor College of Medicine and Children’s Research Institute at UT Southwestern. We thank the University of Virginia Center for Research in Reproduction for measuring serum hormone levels. This work is dedicated to Nicole Ryan who passed away during the study.

Author information

Author notes

    • Nicole Ryan

    Deceased.

Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Daisuke Nakada
    • , Nicole Ryan
    • , Ayumi Kitano
    • , Yusuke Saitoh
    •  & Makiko Takeichi
  2. Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, USA

    • Daisuke Nakada
  3. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA

    • Daisuke Nakada
  4. Howard Hughes Medical Institute, Department of Pediatrics, and Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Hideyuki Oguro
    •  & Sean J. Morrison
  5. Life Sciences Institute, Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Boaz P. Levi
    •  & George R. Wendt

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Contributions

D.N., H.O. and B.P.L. designed and performed most experiments. G.R.W., A.K., N.R., Y.S. and M.T. performed some experiments with D.N. D.N. and S.J.M. analysed results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Daisuke Nakada or Sean J. Morrison.

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DOI

https://doi.org/10.1038/nature12932

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