Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBER-CV), Spain.
Cell Stem Cell. 2019 Sep 5;25(3):407-418.e6. doi: 10.1016/j.stem.2019.06.007. Epub 2019 Jul 11.
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
造血干细胞（HSCs）驻留在骨髓（BM）中，随着年龄的增长而积累，但功能受损。然而，HSC 内在和外在的衰老机制的作用仍存在争议。巨核细胞促进邻近 HSCs 的静止。然而，巨核细胞-HSC 相互作用在病理/自然衰老过程中是否发生变化尚不清楚。Hutchinson-Gilford 早老症中的过早衰老重现了生理衰老的特征，但这些是否是由于干细胞或龛细胞的改变引起的尚不清楚。在这里，我们表明 BM 微环境促进了过早/生理衰老时的骨髓造血。在生理衰老过程中，HSC 支持的龛位在靠近骨骼的地方减少，但在远离骨骼的地方进一步扩展。增加的 BM 去甲肾上腺素能神经支配促进了β-肾上腺素能受体（AR）-白细胞介素 6 依赖性巨核细胞生成。β-AR-Nos1 活性的降低与骨内膜龛的减少以及巨核细胞与窦状隙的附着减少相关。然而，用β-AR 激动剂慢性治疗早老症小鼠可减少过早的髓样细胞和 HSC 扩增，并恢复 HSCs 与巨核细胞的近端关联。因此，BM 龛位的正常/过早衰老会促进髓样细胞的扩增，并且可以通过靶向微环境来改善。
