Lead exposure suppresses the Wnt3a/β-catenin signaling to increase the quiescence of hematopoietic stem cells via reducing the expression of CD70 on bone marrow-resident macrophages

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 wk 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 (UCB) 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.

Ex Vivo Evaluation of the Function of Hematopoietic Stem Cells in Toxicology of Metals

“…Numerous signal pathways have been demonstrated to significantly impact the function of HSCs (Ghosh & Kapur, 2017;Kasbekar et al, 2023). For example, the canonical Wnt signaling drives the proliferation of HSCs, and the non-canonical Wnt signaling promotes myelopoiesis while suppressing lymphopoiesis in HSCs (Florian et al, 2012;López-Ruano et al, 2015;Zhao et al, 2018;Zhao et al, 2023). A direct action and/or an indirect action of a metal may impact certain signaling pathways to alter the behavior of HSCs (Liu et al, 2023;Zhao et al, 2018;Zhao et al, 2023).…”

“…For example, the canonical Wnt signaling drives the proliferation of HSCs, and the non-canonical Wnt signaling promotes myelopoiesis while suppressing lymphopoiesis in HSCs (Florian et al, 2012;López-Ruano et al, 2015;Zhao et al, 2018;Zhao et al, 2023). A direct action and/or an indirect action of a metal may impact certain signaling pathways to alter the behavior of HSCs (Liu et al, 2023;Zhao et al, 2018;Zhao et al, 2023). Thus, investigating the signaling pathways responsible for alteration of HSCs behavior is a pivotal aspect for elucidating the mechanisms of the immune and hematopoietic toxicology of metals.…”

“…Hematopoietic stem cells (HSCs), the progenitor of all blood cells, are able to self‐renew and differentiate into all types of immune cells, as well as erythrocytes and platelets (Metcalf, 2007). Our studies have indicated that metals in the environment can significantly impair the function of HSCs, thereby causing aberrant production of mature immune cells in mice and in humans (Li, Yang, Zhao et al., 2018; Li, Yang, Zhang et al., 2018; Zhang et al., 2016; Zhao et al., 2022; Zhao et al., 2018; Zhao et al., 2021; Zhao et al., 2023). For example, Pb in synergy with IFNγ acts on bone marrow (BM)‐resident macrophages to inhibit Wnt3a/β‐catenin signaling, increasing the quiescence of HSCs (Zhao et al., 2021; Zhao et al., 2023).…”

“…Our studies have indicated that metals in the environment can significantly impair the function of HSCs, thereby causing aberrant production of mature immune cells in mice and in humans (Li, Yang, Zhao et al., 2018; Li, Yang, Zhang et al., 2018; Zhang et al., 2016; Zhao et al., 2022; Zhao et al., 2018; Zhao et al., 2021; Zhao et al., 2023). For example, Pb in synergy with IFNγ acts on bone marrow (BM)‐resident macrophages to inhibit Wnt3a/β‐catenin signaling, increasing the quiescence of HSCs (Zhao et al., 2021; Zhao et al., 2023). Cd activates Wnt5a/Cdc42/Ca 2+ signaling to switch the metabolism pattern of HSCs from glycolysis to mitochondrial oxidative phosphorylation, increasing myelopoiesis at the expense of lymphopoiesis in mice (Zhang et al., 2016; Zhao et al., 2022; Zhao et al., 2018).…”