Cadmium exposure reprograms energy metabolism of hematopoietic stem cells to promote myelopoiesis at the expense of lymphopoiesis in mice

Abstract

Cadmium (Cd) is a highly toxic heavy metal in our living environment. Hematopoietic stem cells (HSC) are ancestors for all blood cells. Therefore understanding the impact of Cd on HSC is significant for public health. The aim of this study was to investigate the impact of Cd2+ on energy metabolism of HSC and its involvement in hematopoiesis. Wild-type C57BL/6 mice were treated with 10 ppm of Cd2+ via drinking water for 3 months, and thereafter glycolysis and mitochondrial (MT) oxidative phosphorylation (OXPHOS) of HSC in the bone marrow (BM) and their impact on hematopoiesis were evaluated. After Cd2+ treatment, HSC had reduced lactate dehydrogenase (LDH) activity and lactate production while having increased pyruvate dehydrogenase (PDH) activity, MT membrane potential, ATP production, oxygen (O2) consumption and reactive oxygen species (ROS), indicating that Cd2+ switched the pattern of energy metabolism from glycolysis to OXPHOS in HSC. Moreover, Cd2+ switch of HSC energy metabolism was critically dependent on Wnt5a/Cdc42/calcium (Ca2+) signaling triggered by a direct action of Cd2+ on HSC. To test the biological significance of Cd2+ impact on HSC energy metabolism, HSC were intervened for Ca2+, OXPHOS, or ROS in vitro, and thereafter the HSC were transplanted into lethally irradiated recipients to reconstitute the immune system; the transplantation assay indicated that Ca2+-dependent MT OXPHOS dominated the skewed myelopoiesis of HSC by Cd2+ exposure. Collectively, we revealed that Cd2+ exposure activated Wnt5a/Cdc42/Ca2+ signaling to reprogram the energy metabolism of HSC to drive myelopoiesis at the expense of lymphopoiesis.

Keywords

• Cadmium
• Hematopoietic stem cells
• Energy metabolism
• Glycolysis
• Mitochondrial oxidative phosphorylation
• Myelopoiesis