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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抑制黄体生成素可增强造血损伤后 HSC 的恢复。


对于保护造血干细胞 (HSC) 库并在癌症治疗或意外暴露造成的辐射损伤后再生造血功能的新策略，存在大量未满足的临床需求。越来越多的证据表明，性激素除了促进性二态性之外，还调节造血干细胞的自我更新、分化和增殖。我们和其他人之前曾报道过，性类固醇消融可促进老年和免疫缺陷小鼠的骨髓 (BM) 淋巴细胞生成和 HSC 恢复。在这里，我们发现黄体生成素 (LH) 释放激素拮抗剂 (LHRH-Ant) 目前在临床上广泛用于性类固醇抑制，在注射致命剂量的总剂量 24 小时后，可促进造血恢复和小鼠存活。身体照射（L-TBI）。出乎意料的是，这种保护作用与性类固醇无关，而是依赖于 LH 水平的抑制。人类和小鼠长期自我更新的 HSC (LT-HSC) 表达高水平的 LH/绒毛膜促性腺激素受体 (LHCGR)，并在 LH 刺激时在体外扩增。相反，L-TBI 后 LH 的抑制抑制了 HSC 进入细胞周期，从而促进 HSC 静止并保护细胞免于耗竭。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。