Letter

Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury

  • Nature Medicine volume 24, pages 239246 (2018)
  • doi:10.1038/nm.4470
  • Download Citation
Received:
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Published:

Abstract

There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure1,2. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation3,4,5. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice5,6,7. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.

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Change history

  • Corrected online 22 January 2018

    In the version of this article initially published online, the phrase "ex vitro" appears in the abstract. This should be "ex vivo". The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We gratefully acknowledge M. Calafiore, H. Jay, J. Gupta, and E. Levy for technical assistance; A. Gomes for assistance with statistical analysis; and the MSKCC Research Animal Resource Center for excellent animal care. We also gratefully acknowledge C. Delaney (Fred Hutchinson Cancer Research Center) for providing UCB units and K.J. Mori (Niigata University) for providing cells. This research was supported by National Institutes of Health awards R00-CA176376 (J.A.D.), R01-HL069929 (M.R.M.v.d.B.), R01-AI080455 (M.R.M.v.d.B.), R01-AI101406 (M.R.M.v.d.B.), P30 CA008748 (C. Thompson, Memorial Sloan Kettering Cancer Center), Project 4 (M.R.M.v.d.B.) of P01-CA023766 (R.J. O'Reilly, Memorial Sloan Kettering Cancer Center), 1R01HL123340-01A1 (K.H. Cadwell, New York University) and Project 2 (M.R.M.v.d.B. and J.A.D.) of P01-AG52359 (J. Nikolich-Zugich, University of Arizona). Support was also received from The Lymphoma Foundation (M.R.M.v.d.B.), The Susan and Peter Solomon Divisional Genomics Program (M.R.M.v.d.B.), and MSKCC Cycle for Survival (M.R.M.v.d.B.). This project received funding from the European Union's Seventh Framework Programme for Research, Technological Development and Demonstration under grant agreement 602587 (Project 7, M.R.M.v.d.B.). This research was also supported by the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center (M.R.M.v.d.B., codirector). E.V. was supported by fellowships from the Italian Foundation for Cancer Research, the Italian Society of Pharmacology, and an American Society of Bone Marrow Transplantation new investigator award. J.A.D. was also supported by a C.J. Martin fellowship from the Australian National Health and Medical Research Council, a Scholar Award from the American Society of Hematology, and the Mechtild Harf Research Grant from the DKMS Foundation for Giving Life. J.J.T. was also supported by a Dorris J. Hutchison Student Fellowship from the Sloan Kettering Institute. T.W. was supported by a Boehringer Ingelheim Fonds MD fellowship.

Author information

Author notes

    • Marcel R M van den Brink
    •  & Jarrod A Dudakov

    These authors jointly directed this work

Affiliations

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

    • Enrico Velardi
    • , Jennifer J Tsai
    • , Kimon V Argyropoulos
    • , Lauren F Young
    • , Amina Lazrak
    • , Odette M Smith
    • , Sophie Lieberman
    • , Fabiana Kreines
    • , Yusuke Shono
    • , Tobias Wertheimer
    • , Alan M Hanash
    •  & Marcel R M van den Brink
  2. Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.

    • Enrico Velardi
  3. Program in Immunology, Clinical Research Division and Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Jennifer J Tsai
    • , Kirsten Cooper
    •  & Jarrod A Dudakov
  4. Department of Immunology, University of Washington, Seattle, Washington, USA.

    • Jennifer J Tsai
    • , Kirsten Cooper
    •  & Jarrod A Dudakov
  5. Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Stefan Radtke
    •  & Hans-Peter Kiem
  6. Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

    • Stefan Radtke
  7. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Shieh Jae-Hung
    •  & Malcolm A Moore
  8. Departments of Genomic Medicine and Stem Cell Transplantation Cellular Therapy, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Robert R Jenq
  9. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Alan M Hanash
    •  & Marcel R M van den Brink
  10. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA.

    • Prema Narayan
  11. Department of OB/GYN & Women′s Health, University of Louisville School of Medicine, Louisville, Kentucky, USA.

    • Zhenmin Lei
  12. Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

    • Hans-Peter Kiem
  13. Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.

    • Hans-Peter Kiem
  14. Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, New York, USA.

    • Marcel R M van den Brink

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Contributions

E.V. contributed to the design, execution, analysis, and interpretation of the studies, and the drafting of the manuscript; J.J.T. contributed to the execution and interpretation of the studies, and the drafting of the manuscript; S.R. performed studies on human UCBs under the guidance of H.-P.K.; K.C. performed studies on LHCGR expression; S.J.-H. performed studies on mouse CAFCs and CFCs under the guidance of M.A.M.; K.V.A., S.J.-H., L.F.Y., A.L., O.M.S., S.L., and F.K. performed, analyzed, and helped in interpreting experiments; Y.S., T.W., R.R.J., and A.M.H. helped in interpreting experiments; P.N. and Z.L. provided KiLHRD582G and Lhcgr-KO mice, respectively; and M.R.M.v.d.B. and J.A.D. designed, interpreted and supervised all studies and wrote the manuscript.

Competing interests

A provisional patent application has been filed on the use of LHRH-Ant as a treatment for hematopoietic recovery from radiation injury (US 15/033,178), with E.V., J.A.D., and M.R.M.v.d.B. listed as inventors. A provisional patent application has been filed on the use of LH to create, ablate, and modify primitive stem cell populations (US 62/566,897), with E.V., J.A.D., S.R., H.-P.K., and M.R.M.v.d.B. listed as inventors.

Corresponding authors

Correspondence to Enrico Velardi or Marcel R M van den Brink or Jarrod A Dudakov.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–6 and Supplementary Table 1

  2. 2.

    Life Sciences Reporting Summary