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
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.
References
Dainiak, N. Hematologic consequences of exposure to ionizing radiation. Exp. Hematol. 30, 513–528 (2002).
Anno, G.H., Young, R.W., Bloom, R.M. & Mercier, J.R. Dose response relationships for acute ionizing-radiation lethality. Health Phys. 84, 565–575 (2003).
Mierzejewska, K. et al. Hematopoietic stem/progenitor cells express several functional sex hormone receptors-novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells Dev. 24, 927–937 (2015).
Sánchez-Aguilera, A. et al. Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis. Cell Stem Cell 15, 791–804 (2014).
Nakada, D. et al. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 505, 555–558 (2014).
Dudakov, J.A. et al. Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. J. Immunol. 183, 7084–7094 (2009).
Khong, D.M. et al. Enhanced hematopoietic stem cell function mediates immune regeneration following sex steroid blockade. Stem Cell Rep. 4, 445–458 (2015).
Williams, J.P. et al. Animal models for medical countermeasures to radiation exposure. Radiat. Res. 173, 557–578 (2010).
Koukourakis, M.I. Radiation damage and radioprotectants: new concepts in the era of molecular medicine. Br. J. Radiol. 85, 313–330 (2012).
Goldberg, G.L. et al. Sex steroid ablation enhances immune reconstitution following cytotoxic antineoplastic therapy in young mice. J. Immunol. 184, 6014–6024 (2010).
Dudakov, J.A., Goldberg, G.L., Reiseger, J.J., Chidgey, A.P. & Boyd, R.L. Withdrawal of sex steroids reverses age- and chemotherapy-related defects in bone marrow lymphopoiesis. J. Immunol. 182, 6247–6260 (2009).
Velardi, E. et al. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J. Exp. Med. 211, 2341–2349 (2014).
Katayama, N. et al. Stage-specific expression of c-kit protein by murine hematopoietic progenitors. Blood 82, 2353–2360 (1993).
Li, W., Wang, G., Cui, J., Xue, L. & Cai, L. Low-dose radiation (LDR) induces hematopoietic hormesis: LDR-induced mobilization of hematopoietic progenitor cells into peripheral blood circulation. Exp. Hematol. 32, 1088–1096 (2004).
Meistrich, M.L. Male gonadal toxicity. Pediatr. Blood Cancer 53, 261–266 (2009).
Notta, F. et al. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 333, 218–221 (2011).
Choi, J. & Smitz, J. Luteinizing hormone and human chorionic gonadotropin: origins of difference. Mol. Cell. Endocrinol. 383, 203–213 (2014).
Tsai, J.J. et al. Nrf2 regulates haematopoietic stem cell function. Nat. Cell Biol. 15, 309–316 (2013).
Kharas, M.G. et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 115, 1406–1415 (2010).
Wang, Y.V. et al. Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity. Genes Dev. 25, 1426–1438 (2011).
Wang, Y., Schulte, B.A., LaRue, A.C., Ogawa, M. & Zhou, D. Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 107, 358–366 (2006).
Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).
Johnson, S.M. et al. Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J. Clin. Invest. 120, 2528–2536 (2010).
Chen, C. et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J. Exp. Med. 205, 2397–2408 (2008).
Himburg, H.A. et al. Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J. Clin. Invest. 124, 4753–4758 (2014).
Shiraishi, K. & Ascoli, M. Lutropin/choriogonadotropin stimulate the proliferation of primary cultures of rat Leydig cells through a pathway that involves activation of the extracellularly regulated kinase 1/2 cascade. Endocrinology 148, 3214–3225 (2007).
McGee, S.R. & Narayan, P. Precocious puberty and Leydig cell hyperplasia in male mice with a gain of function mutation in the LH receptor gene. Endocrinology 154, 3900–3913 (2013).
Brenet, F., Kermani, P., Spektor, R., Rafii, S. & Scandura, J.M. TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy. J. Exp. Med. 210, 623–639 (2013).
Zsebo, K.M. et al. Radioprotection of mice by recombinant rat stem cell factor. Proc. Natl. Acad. Sci. USA 89, 9464–9468 (1992).
Goncalves, K.A. et al. Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence of stem and progenitor cells. Cell 166, 894–906 (2016).
Yu, X. et al. HES1 inhibits cycling of hematopoietic progenitor cells via DNA binding. Stem Cells 24, 876–888 (2006).
Opferman, J.T. et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307, 1101–1104 (2005).
Qing, Y., Wang, Z., Bunting, K.D. & Gerson, S.L. Bcl2 overexpression rescues the hematopoietic stem cell defects in Ku70-deficient mice by restoration of quiescence. Blood 123, 1002–1011 (2014).
He, S. et al. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci. Transl. Med. 9, eaal3986 (2017).
Winkler, I.G. et al. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat. Med. 18, 1651–1657 (2012).
van Os, R. et al. A limited role for p21Cip1/Waf1 in maintaining normal hematopoietic stem cell functioning. Stem Cells 25, 836–843 (2007).
Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84–90 (2009).
Shao, L. et al. Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner. Blood 123, 3105–3115 (2014).
Geiger, H., de Haan, G. & Florian, M.C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013).
Essers, M.A. et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009).
Doan, P.L. et al. Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat. Med. 19, 295–304 (2013).
Randall, T.D. & Weissman, I.L. Phenotypic and functional changes induced at the clonal level in hematopoietic stem cells after 5-fluorouracil treatment. Blood 89, 3596–3606 (1997).
Jo, D.Y., Rafii, S., Hamada, T. & Moore, M.A. Chemotaxis of primitive hematopoietic cells in response to stromal cell-derived factor-1. J. Clin. Invest. 105, 101–111 (2000).
Itoh, K. et al. Reproducible establishment of hemopoietic supportive stromal cell lines from murine bone marrow. Exp. Hematol. 17, 145–153 (1989).
Radtke, S., Haworth, K.G. & Kiem, H.P. The frequency of multipotent CD133+CD45RA−CD34+ hematopoietic stem cells is not increased in fetal liver compared with adult stem cell sources. Exp. Hematol. 44, 502–507 (2016).
Faul, F., Erdfelder, E., Buchner, A. & Lang, A.G. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav. Res. Methods 41, 1149–1160 (2009).
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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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.
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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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DOI: https://doi.org/10.1038/nm.4470