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. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. 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.

中文翻译：

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黄体生成素的抑制可增强造血损伤后HSC的恢复。

临床上对满足保护造血干细胞（HSC）池并在癌症治疗或意外暴露造成放射损伤后再生造血功能的新策略的需求仍未得到满足。越来越多的证据表明，性激素除了具有促进性二态性的作用外，还可以调节HSC的自我更新，分化和增殖。我们和其他人以前曾报道过，性类固醇消融可促进衰老和免疫缺陷小鼠的骨髓（BM）淋巴细胞生成和HSC恢复。在这里，我们发现，目前以促黄体激素（LH）释放激素的拮抗剂（LHRH-Ant）目前在临床上广泛用于抑制性类固醇，而在以致死剂量服用总黄酮后24小时给予身体照射（L-TBI）。不料，这种保护作用不依赖于性类固醇，而是依赖于LH水平的抑制。人和小鼠的长期自我更新HSC（LT-HSC）表达高水平的LH /绒毛膜促性腺激素受体（LHCGR），并在受LH刺激时离体扩增。相反，在L-TBI后抑制LH抑制了HSC进入细胞周期，从而促进HSC静止并保护细胞免于衰竭。这些发现揭示了LH在调节HSC功能中的作用，并为造血损伤后的造血再生提供了新的治疗方法。L-TBI后抑制LH抑制了HSC进入细胞周期，从而促进HSC静止并保护细胞免于衰竭。这些发现揭示了LH在调节HSC功能中的作用，并为造血损伤后的造血再生提供了新的治疗方法。L-TBI后抑制LH抑制了HSC进入细胞周期，从而促进HSC静止并保护细胞免于衰竭。这些发现揭示了LH在调节HSC功能中的作用，并为造血损伤后的造血再生提供了新的治疗方法。