Metabolism of iron and iron oxide nanoparticles in glial cells

Abstract

Iron is an essential metal for mammalian cells catalyzing redox reactions in various metabolic pathways. However, iron can also induce cellular damage due to increased formation of reactive oxygen species (ROS). Among the different brain cell types, oligodendrocytes produce and maintain the myelin sheaths around neuronal axons whereas brain astrocytes participate in a variety of different brain functions such as synaptic signal transduction, regulation of metal homeostasis and detoxification of xenobiotics. In brain, these cells may encounter iron oxide nanoparticles (Fe-NP), since Fe-NP are extensively investigated for biomedical applications. This thesis investigated the metabolism of iron and Fe-NP in glial cells. The oligodendroglial OLN-93 cells express the mRNAs of the protein transferrin, transferrin-receptor and divalent metal transporter 1 for iron uptake as well as the iron storage protein ferritin. The proliferation of these cells depended on the availability of extracellular iron and can be inhibited by iron chelators. Furthermore, OLN-93 cells accumulated substantial amounts of iron from low molecular weight iron salts and Fe-NP. The cell viability was not compromised despite of high intracellular iron concentrations. Moreover, exposure to Fe-NP hardly affected the metabolism of OLN-93 cells. Intracellularly, iron was mobilized from Fe-NP by OLN-93 cells as demonstrated by the increase in proliferation following iron restriction, by the upregulation of ferritin and by the inhibition of Fe-NP-dependent ROS formation by a cell-membrane-permeable iron chelator. Also primary astrocytes took up Fe-NP as shown by increased cellular iron contents and electron microscopy. Both OLN-93 cells and astrocytes accumulated iron from Fe-NP in comparable amounts, showed similar time- and concentration-dependencies of iron accumulation and stored iron in ferritin. These observations suggest that the uptake and the cellular fate of Fe-NP are similar in OLN-93 cells and astrocytes.