title: Ferritin stimulates oligodendrocyte genesis in the adult spinal cord and can be transferred from macrophages to NG2 cells in vivo.
abstract: Injured CNS tissue often contains elevated iron and its storage protein ferritin, which may exacerbate tissue damage through pro-oxidative mechanisms. Therefore, therapeutic studies often target iron reduction as a neuroprotective strategy. However, iron may be crucial for oligodendrocyte replacement and remyelination. For instance, we previously showed that intraspinal toll-like receptor 4 macrophage activation induced the generation of new ferritin-positive oligodendrocytes, and that iron chelation significantly reduced this oligodendrogenic response. Since macrophages can secrete ferritin, we hypothesize that ferritin is a macrophage-derived signal that promotes oligodendrogenesis. To test this, we microinjected ferritin into intact adult rat spinal cords. Within 6 h, NG2+ progenitor cells proliferated and accumulated ferritin. By 3 d, many of these cells had differentiated into new oligodendrocytes. However, acute neuron and oligodendrocyte toxicity occurred in gray matter. Interestingly, ferritin-positive NG2 cells and macrophages accumulated in the area of cell loss, revealing that NG2 cells thrive in an environment that is toxic to other CNS cells. To test whether ferritin can be transferred from macrophages to NG2 cells in vivo, we loaded macrophages with fluorescent ferritin then transplanted them into intact spinal white matter. Within 3-6 d, proliferating NG2 cells migrated into the macrophage transplants and accumulated fluorescently labeled ferritin. These results show that activated macrophages can be an in vivo source of ferritin for NG2 cells, which induces their proliferation and differentiation into new oligodendrocytes. This work has relevance for conditions in which iron-mediated injury and/or repair likely occur, such as hemorrhage, stroke, spinal cord injury, aging, Parkinson's disease, and Alzheimer's disease.
authors.affiliation: The Neuroscience Graduate Studies Program, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Schonberg
authors.forename: Evan Z
authors.initials: EZ
authors.lastname: Goldstein
authors.forename: Fatma Rezan
authors.initials: FR
authors.lastname: Sahinkaya
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
authors.forename: Dana M
authors.initials: DM
authors.lastname: McTigue
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D000941:Antigens / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005293:Ferritins / Q000378:metabolism / Q000494:pharmacology*; D005732:Gangliosides / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects; D008845:Microinjections / Q000379:methods; D009836:Oligodendroglia / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology* / Q000187:drug effects; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000880:Anthraquinones; D000941:Antigens; D001973:Bromodeoxyuridine; D039481:CD11b Antigen; D005293:Ferritins; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D010751:Phosphopyruvate Hydratase; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C520537:1,5-bis((2-(methylamino)ethyl)amino)-4,8-dihydroxyanthracene-9,10-dione; C062875:ganglioside A2B5