Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China.
Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
Toxicol Sci. 2023 Aug 29;195(1):123-142. doi: 10.1093/toxsci/kfad067.
Lead (Pb) is a heavy metal highly toxic to human health in the environment. The aim of this study was to investigate the mechanism of Pb impact on the quiescence of hematopoietic stem cells (HSC). WT C57BL/6 (B6) mice treated with 1250 ppm Pb via drinking water for 8 weeks had increased the quiescence of HSC in the bone marrow (BM), which was caused by the suppressed activation of the Wnt3a/β-catenin signaling. Mechanically, a synergistic action of Pb and IFNγ on BM-resident macrophages (BM-Mφ) reduced their surface expression of CD70, which thereby dampened the Wnt3a/β-catenin signaling to suppress the proliferation of HSC in mice. In addition, a joint action of Pb and IFNγ also suppressed the expression of CD70 on human Mφ to impair the Wnt3a/β-catenin signaling and reduce the proliferation of human HSC purified from umbilical cord blood of healthy donors. Moreover, correlation analyses showed that the blood Pb concentration was or tended to be positively associated with the quiescence of HSC, and was or tended to be negatively associated with the activation of the Wnt3a/β-catenin signaling in HSC in human subjects occupationally exposed to Pb. Collectively, these data indicate that an occupationally relevant level of Pb exposure suppresses the Wnt3a/β-catenin signaling to increase the quiescence of HSC via reducing the expression of CD70 on BM-Mφ in both mice and humans.
铅（Pb）是一种对环境中人类健康有高度毒性的重金属。本研究旨在探讨 Pb 对造血干细胞（HSC）静止的影响机制。通过饮用水给予 WT C57BL/6（B6）小鼠 1250ppm Pb 处理 8 周，导致骨髓（BM）中 HSC 的静止增加，这是由于 Wnt3a/β-catenin 信号的激活受到抑制。从机制上讲，Pb 和 IFNγ 对 BM 驻留巨噬细胞（BM-Mφ）的协同作用降低了其表面 CD70 的表达，从而抑制了 Wnt3a/β-catenin 信号，抑制了小鼠 HSC 的增殖。此外，Pb 和 IFNγ 的联合作用也抑制了人 Mφ 上 CD70 的表达，损害了 Wnt3a/β-catenin 信号，减少了从健康供体脐带血中纯化的人 HSC 的增殖。此外，相关性分析表明，职业性 Pb 暴露人群的血液 Pb 浓度与 HSC 的静止呈正相关或有正相关趋势，与 HSC 中 Wnt3a/β-catenin 信号的激活呈负相关或有负相关趋势。总之，这些数据表明，职业相关水平的 Pb 暴露通过降低 BM-Mφ 上 CD70 的表达，抑制 Wnt3a/β-catenin 信号，增加小鼠和人类 HSC 的静止。
