Zhao Yifan, Li Qian, Zhu Tingting, He Jinyi, Xue Peng, Zheng Weiwei, Yao Ye, Qu Weidong, Zhou Zhijun, Lu Rongzhu, Zhou Zhou, He Rui, He Miao, Zhang Yubin
School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China.
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
Toxicol Sci. 2021 Apr 12;180(2):369-382. doi: 10.1093/toxsci/kfab001.
Lead (Pb) is a highly toxic heavy metal that broadly exists in our living environment. Although Pb has been shown to influence the development of immune cells, to date, the impact of Pb on hematopoietic stem cells (HSCs) in the bone marrow (BM) remains unknown. As people are ubiquitously exposed to Pb and HSC are essential for human health, understanding the impact of Pb on HSC is significant for public health. In this study, we found that wild-type B6 mice treated with 1250 ppm Pb, but not 125 ppm Pb via drinking water for 8 weeks had increased quiescence of HSC in the BM. Functional analyses demonstrated that wild-type mice treated with 1250 ppm Pb had increased potential for HSC to repopulate the immune system and engraft to the niche in the BM under a competitive chimeric microenvironment of lethally irradiated recipients. Moreover, we found that Pb-increased quiescence of HSC critically relied on a synergetic action of Pb and interferon γ (IFNγ) on BM-resident macrophages (BM-MΦ), but not a direct action of Pb on HSC. Specifically, in steady state, BM-MΦ promoted HSC proliferation; and upon Pb treatment, IFNγ was induced in the BM, and thereafter Pb in synergism with IFNγ acted on BM-MΦ to cause BM-MΦ to become suppressive for HSC proliferation, thus leading to increased quiescence of HSC. Our study suggests that Pb increased the quiescence of HSC via a synergetic action of Pb and IFNγ on BM-MΦ, which was previously unrecognized toxicity of Pb.
铅（Pb）是一种剧毒重金属，广泛存在于我们的生活环境中。尽管已有研究表明铅会影响免疫细胞的发育，但迄今为止，铅对骨髓（BM）中造血干细胞（HSCs）的影响仍不清楚。由于人们普遍接触铅，且造血干细胞对人类健康至关重要，因此了解铅对造血干细胞的影响对公共卫生具有重要意义。在本研究中，我们发现，通过饮用水给予1250 ppm铅处理8周的野生型B6小鼠，而非给予125 ppm铅处理的小鼠，其骨髓中造血干细胞的静止状态增加。功能分析表明，在致死性照射受体的竞争性嵌合微环境下，给予1250 ppm铅处理的野生型小鼠造血干细胞重建免疫系统和植入骨髓生态位的潜力增加。此外，我们发现铅增加造血干细胞的静止状态关键依赖于铅和干扰素γ（IFNγ）对骨髓驻留巨噬细胞（BM-MΦ）的协同作用，而非铅对造血干细胞的直接作用。具体而言，在稳态下，骨髓驻留巨噬细胞促进造血干细胞增殖；在铅处理后，骨髓中诱导产生干扰素γ，随后铅与干扰素γ协同作用于骨髓驻留巨噬细胞，使骨髓驻留巨噬细胞对造血干细胞增殖产生抑制作用，从而导致造血干细胞静止状态增加。我们的研究表明，铅通过铅和干扰素γ对骨髓驻留巨噬细胞的协同作用增加造血干细胞的静止状态，这是铅以前未被认识到的毒性。
