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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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.
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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