Abstract：
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.
摘要：
铅(Pb)是环境中对人体健康剧毒的重金属。本研究的目的是探讨铅对造血干细胞（HSC）静止的影响机制。WTC57BL/6（B6）小鼠通过饮用水用1250ppmPb处理8周增加了骨髓（BM）中HSC的静止期，这是由Wnt3a/β-catenin信号传导的抑制激活引起的。机械上,Pb和IFNγ对BM常驻巨噬细胞（BM-Mφ）的协同作用降低了其CD70的表面表达，从而抑制了Wnt3a/β-catenin信号传导以抑制小鼠HSC的增殖。此外,Pb和IFNγ的共同作用还抑制了CD70在人Mφ上的表达，从而损害了Wnt3a/β-catenin信号传导并减少了从健康供体的脐带血（UCB）中纯化的人HSC的增殖。此外，相关分析表明，血铅浓度与HSC的静止呈正相关或趋于正相关，并且在职业暴露于Pb的人类受试者中，与HSC中Wnt3a/β-catenin信号的激活呈负相关。总的来说，这些数据表明，与职业相关的铅暴露水平通过减少小鼠和人类BM-Mφ上CD70的表达来抑制Wnt3a/β-catenin信号传导以增加HSC的静止。
