Iron overload regulate the cytokine of mesenchymal stromal cells through ROS/HIF-1α pathway in Myelodysplastic syndromes

Abstract

Iron overload is a significant feature of myelodysplastic syndromes (MDS) patients due to ineffective hematopoiesis and transfusion dependence. Excess iron results in organ dysfunction through the generation of reactive oxygen species (ROS) which can cause oxidative stress even mutation. Mesenchymal stromal cells (MSCs) are responsible for supporting and regulating hematopoiesis, whether MSCs is involved in the pathogenesis of MDS still need further elucidation. Hypoxia-inducible factors-1 (HIF-1) is an integral signal of inflammation that has been shown to up-regulating in MDS patient. We found that MDS-derived MSC had disorganized clones and increased level of apoptosis (n = 53). Iron transportation-related gene, such as DMT1 and ZIP14, and ROS level were increased in iron overload-MDS-MSC (n = 23). HIF-1a, as a crucial part of HIF-1, was also elevated in iron overload-group and PHD2 involved in the degradation of HIF-1a was reduced. Furthermore, HIF-1 downstream cytokines such IL-6, IL-8, TGF-βand VEGF that were also involved in the pathogenesis of MDS were increased in IO-MDS-MSC. When treated with DFO and NAC for iron chelation and antioxidation, the level of HIF-1a and related cytokines could decrease. We conclude that iron overload regulates the cytokine of mesenchymal stromal cells through ROS/HIF-1α pathway in Myelodysplastic syndromes, result in dysfunction of MSC and damage of microenvironment that may be involved in the pathogenesis of MDS.