Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury

  • A Corrigendum to this article was published on 01 April 2018

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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Figure 1: LHRH antagonism improves hematopoietic recovery and mouse survival after L-TBI.
Figure 2: The regenerative benefit of LHRH-Ant after L-TBI is dependent on suppression of LH, not sex steroids.
Figure 3: LH directly promotes HSC expansion, and its suppression after hematopoietic insult decreases HSC entry into the cell cycle.
Figure 4: LH suppression promotes quiescence and protects HSCs from exhaustion.

Change history

  • 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.

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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.

Corresponding authors

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

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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.

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Velardi, E., Tsai, J., Radtke, S. et al. Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24, 239–246 (2018). https://doi.org/10.1038/nm.4470

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