H‐ferritin is the major source of iron for oligodendrocytes

Abstract

There is a critical relationship between oligodendrocyte development, myelin production, and iron bioavailability. Iron deficiency leads to hypomyelination both in humans and animal models, and the neurological sequelae of hypomyelination are significant. Therefore, understanding molecular mechanisms of iron import into oligodendrocytes is necessary for devising effective strategies for iron supplementation. Although transferrin has been considered as an essential component of oligodendrocyte media in culture, oligodendrocytes in vivo lack transferrin receptors. We have established that receptors for H-ferritin (HF) exist on cells of oligodendroglial lineage and that uptake of extracellular HF by oligodendrocyte progenitors is via receptor mediated endocytosis. These data strongly argue that ferritin is a major source of iron for oligodendrocytes. In this study, we demonstrate that media deficient in transferrin results in loss of viability of oligodendrocyte progenitors in culture. Cell loss could be prevented by supplementing the media with HF. Moreover, the addition of extracellular HF stimulates development of oligodendrocyte progenitor cells (OPCs) by increasing expression of myelin basic protein (MBP) and olig2 proteins without increasing their proliferation. The effect of HF on the OPCs could be mimicked by addition of membrane permeable 3,5,5-trimethylhexanoyl ferrocene (TMH-Fe) as an iron source to the media, but not membrane-impermeable ferric ammonium citrate. Overall, therefore, our results demonstrate the importance of iron for OPCs viability and differentiation and identify extracellular HF as a critical source of iron for oligodendrocytes. Given that ferritin receptors, but not transferrin receptors can be demonstrated on oligodendrocytes in vivo, the delivery of iron to oligodendrocytes via ferritin may be the more biological relevant delivery system.

Cerebrospinal Fluid Markers of Macrophage and Lymphocyte Activation After Traumatic Brain Injury in Children

“…CSF ferritin was noted to be higher during the first time point assessed (17±10 h), whereas sCD163 was higher during the second time point (72±15 h). This could be consistent with early release of ferritin from damaged and activated microglia (24) or oligodendrocytes (25), with a later increase in sCD163 from systemic, infiltrating macrophages or perivascular microglia scavenging hemoglobin (26). A clinical study has shown early increases (<12 h) in ferritin within contusions after TBI in humans (27), whereas experimental data suggest a more delayed increase (72–96 h) in CD163-positive macrophages/microglia after TBI in rats (28).…”

Maternal Immune Activation Induces Changes in Myelin and Metabolic Proteins, Some of Which Can Be Prevented with Risperidone in Adolescence

“…We found ferritin heavy chain, which is expressed abundantly in oligodendrocytes [66] , to be downregulated following poly(I:C). These findings are consistent with the possibil-ity that prenatal inflammation may act to reduce iron availability and so contribute to myelin dysregulation.…”

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

“…Ferritin molecules trafficked across the BBB may be sequestered by oligodendrocytes which accumulate ferritin during postnatal ontogenesis [1]. Oligodendrocytes, which largely utilize FHC [156], may use the ferritin-iron for the synthesis of myelin [2]. Peak myelination by oligodendrocytes occurs at P15, shortly after ferritin trafficking across the BBB ceases [10, 157].…”