Université de Paris, Université Paris Saclay, INSERM-CEA, Stabilité Génétique Cellules Souches et Radiations, Laboratoire Réparation et Transcription dans les cellules Souches (LRTS), Institut de Radiobiologie Cellulaire et Moléculaire (iRCM), Institut de Biologie François Jacob (IBFJ), Direction de la Recherche Fondamentale (DRF), Fontenay-aux-Roses, France.
Blood Adv. 2022 Mar 22;6(6):1766-1779. doi: 10.1182/bloodadvances.2021005983.
Bone marrow (BM) resident macrophages interact with a population of long-term hematopoietic stem cells (LT-HSCs) but their role on LT-HSC properties after stress is not well defined. Here, we show that a 2 Gy-total body irradiation (TBI)-mediated death of LT-HSCs is associated with increased percentages of LT-HSCs with reactive oxygen species (ROS) and of BM resident macrophages producing nitric oxide (NO), resulting in an increased percentage of LT-HSCs with endogenous cytotoxic peroxynitrites. Pharmacological or genetic depletion of BM resident macrophages impairs the radio-induced increases in the percentage of both ROS+ LT-HSCs and peroxynitrite+ LT-HSCs and results in a complete recovery of a functional pool of LT-HSCs. Finally, we show that after a 2 Gy-TBI, a specific decrease of NO production by BM resident macrophages improves the LT-HSC recovery, whereas an exogenous NO delivery decreases the LT-HSC compartment. Altogether, these results show that BM resident macrophages are involved in the response of LT-HSCs to a 2 Gy-TBI and suggest that regulation of NO production can be used to modulate some deleterious effects of a TBI on LT-HSCs.
骨髓（BM）常驻巨噬细胞与一群长期造血干细胞（LT-HSCs）相互作用，但它们在应激后对 LT-HSC 特性的作用尚未明确界定。在这里，我们表明，2 Gy 全身照射（TBI）介导的 LT-HSC 死亡与具有活性氧（ROS）的 LT-HSC 百分比增加以及产生一氧化氮（NO）的 BM 常驻巨噬细胞百分比增加有关，导致具有内源性细胞毒性过氧亚硝酸盐的 LT-HSC 百分比增加。BM 常驻巨噬细胞的药理学或遗传学耗竭会损害 LT-HSCs 中 ROS+和过氧亚硝酸盐+的百分比增加，并导致 LT-HSC 的功能池完全恢复。最后，我们表明，在 2 Gy-TBI 后，BM 常驻巨噬细胞中 NO 产生的特定减少可改善 LT-HSC 的恢复，而外源性 NO 输送则减少 LT-HSC 区室。总而言之，这些结果表明，BM 常驻巨噬细胞参与了 LT-HSCs 对 2 Gy-TBI 的反应，并表明可以调节 NO 产生来调节 TBI 对 LT-HSCs 的一些有害影响。
