Nature Medicine 2018-01-08

Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury

Enrico Velardi, Jennifer J Tsai, Stefan Radtke, Kirsten Cooper, Kimon V Argyropoulos, Shieh Jae-Hung, Lauren F Young, Amina Lazrak, Odette M Smith, Sophie Lieberman, Fabiana Kreines, Yusuke Shono, Tobias Wertheimer, Robert R Jenq, Alan M Hanash, Prema Narayan, Zhenmin Lei, Malcolm A Moore, Hans-Peter Kiem, Marcel R M van den Brink, Jarrod A Dudakov

Index: 10.1038/nm.4470

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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 vitro 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.