Journal
NATURE MEDICINE
Volume 24, Issue 2, Pages 239-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4470
Keywords
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Funding
- National Institutes of Health [R00-CA176376, R01-HL069929, R01-AI080455, R01-AI101406, P30 CA008748, P01-CA023766, 1R01HL123340-01A1, P01-AG52359]
- Lymphoma Foundation
- Susan and Peter Solomon Divisional Genomics Program
- MSKCC Cycle for Survival
- European Union's Seventh Framework Programme for Research, Technological Development and Demonstration [602587]
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center
- Italian Foundation for Cancer Research
- Italian Society of Pharmacology
- American Society of Bone Marrow Transplantation new investigator award
- C.J. Martin fellowship from the Australian National Health and Medical Research Council
- Scholar Award from the American Society of Hematology
- Mechtild Harf Research Grant from the DKMS Foundation for Giving Life
- Dorris J. Hutchison Student Fellowship from the Sloan Kettering Institute
- Boehringer Ingelheim Fonds MD fellowship
- NATIONAL CANCER INSTITUTE [R00CA176376, P01CA023766, P30CA008748, P30CA016672] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL069929, K08HL115355, R01HL123340] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI100288, R01AI101406, R01AI080455] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG052359] Funding Source: NIH RePORTER
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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 exposure(1,2). Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation(3-5). We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice(5-7). 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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