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Molecular Neurobiology

, Volume 55, Issue 2, pp 1068–1081 | Cite as

Iron Availability Compromises Not Only Oligodendrocytes But Also Astrocytes and Microglial Cells

  • Maria Victoria Rosato-Siri
  • Leandro Marziali
  • María Eugenia Guitart
  • Maria Elvira Badaracco
  • Mariana Puntel
  • Fernando Pitossi
  • Jorge Correale
  • Juana Maria Pasquini
Article

Abstract

When disrupted, iron homeostasis negatively impacts oligodendrocyte (OLG) differentiation and impairs myelination. To better understand myelin formation and OLG maturation, in vivo and in vitro studies were conducted to evaluate the effect of iron deficiency (ID) not only on OLG maturation but also on astrocytes (AST) and microglial cells (MG). In vivo experiments in an ID model were carried out to describe maturational events during OLG and AST development and the reactive profile of MG during myelination when iron availability is lower than normal. In turn, in vitro assays were conducted to explore proliferating and maturational states of each glial cell type derived from control or ID conditions. Studies targeted NG2, PDGFRα, CNPAse, CC1, and MBP expression in OLG, GFAP and S100 expression in AST, and CD11b, ED1, and cytokine expression in MG, as well as BrDU incorporation in the three cell types. Our results show that ID affected OLG development at early stages, not only reducing their maturation capacity but also increasing their proliferation and affecting their morphological complexity. AST ID proliferated more than control ones and were more immature, much like OLG. Cytokine expression in ID animals reflected an anti-inflammatory state which probably influenced OLG maturation. These results show that ID conditions alter all glial cells and may impact myelin formation, which could be regulated by a mechanism involving a cross talk between AST, MG, and oligodendrocyte progenitors (OPC).

Keywords

Iron deficiency Oligodendrocyte maturation Astrocyte response Microglial cell activation Hypomyelination 

Notes

Acknowledgements

This work was supported by generous funding from Universidad de Buenos Aires; grant number: 20020100100395. We are especially grateful to Marianela Vence for her special dedication and technical assistance with experimental animals and to María Marta Rancez for her helpful insights.

Compliance with Ethical Standards

Conflict of Interest

The authors have no conflict of interest to declare.

References

  1. 1.
    Beard JL (2008) Why iron deficiency is important in infant development. J Nutr 138:2534–2536CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T (2006) Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev 64:S34–S43 discussion S72-91CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Piñero DJ, Li NQ, Connor JR, Beard JL (2000) Variations in dietary iron alter brain iron metabolism in developing rats. J Nutr 130:254–263CrossRefPubMedGoogle Scholar
  4. 4.
    Badaracco ME, Ortiz EH, Soto EF, Connor J, Pasquini JM (2008) Effect of transferrin on hypomyelination induced by iron deficiency. J Neurosci Res 86:2663–2673CrossRefPubMedGoogle Scholar
  5. 5.
    Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981–990CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Johnstone D, Milward EA (2010) Genome-wide microarray analysis of brain gene expression in mice on a short-term high iron diet. Neurochem Int 56:856–863CrossRefPubMedGoogle Scholar
  7. 7.
    Meguro R, Asano Y, Odagiri S, Li C, Shoumura K (2008) Cellular and subcellular localizations of nonheme ferric and ferrous iron in the rat brain: a light and electron microscopic study by the perfusion-Perls and -Turnbull methods. Arch Histol Cytol 71:205–222CrossRefPubMedGoogle Scholar
  8. 8.
    Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR (2009) Oligodendrocytes and myelination: the role of iron. Glia 57:467–478CrossRefPubMedGoogle Scholar
  9. 9.
    Todorich B, Zhang X, Connor JR (2011) H-ferritin is the major source ofironforoligodendrocytes. Glia 59:927–935CrossRefPubMedGoogle Scholar
  10. 10.
    Rosato-Siri MV, Badaracco ME, Ortiz EH, Belforte N, Guardia Clausi M, Soto EF, Bernabeu R, Pasquini JM (2010) Oligodendrogenesis in iron-deficient rats: effect of Apotransferrin. J Neurosc Res. 88:1695–1607Google Scholar
  11. 11.
    Forge JK, Pedchenko TV, LeVine SM (1998) Iron deposits in the central nervous system of SJL mice with experimental allergic encephalomyelitis. Life Sci 63:2271–2284CrossRefPubMedGoogle Scholar
  12. 12.
    Zarruk JG, Berard JL, Passos Dos Santos R, Kroner A, Lee J, Arosio P, David S (2015) Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation. Neurobiol Dis 81:93–107CrossRefPubMedGoogle Scholar
  13. 13.
    Clemente D, Ortega MC, Melero-Jerez C, de Castro F (2013) The effect of glia-glia interactions on oligodendrocyte precursor cell biology during development and in demyelinating diseases. Front Cell Neurosci 7:268CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang SC, Goetz BD, Carré JL, Duncan ID (2001) Reactive microglia in dysmyelination and demyelination. Glia 15:101–109CrossRefGoogle Scholar
  15. 15.
    Zhang X, Surguladze N, Slagle-webb B, Cozzi A, Connor JR (2006) Cellular iron status influences the functional relationship between microglia and astrocytes. Glia 54:795–804CrossRefPubMedGoogle Scholar
  16. 16.
    Albrecht PJ, Murtie JC, Ness JK, Redwine JM, Enterline JR, Armstrong RC, Levison SW (2003) Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production. Neurobiol Dis 13:89–101CrossRefPubMedGoogle Scholar
  17. 17.
    Mason JL, Suzuki K, Chaplin DD, Matsushima GK (2001) Interleukin-1beta promotes repair of the CNS. J Neurosci 21:7046–7052PubMedGoogle Scholar
  18. 18.
    Gudi V, Skuljec J, Yidiz O, Frichert K, Skripuletz T, Moharregh-Khlabani D, Voss E, Wissel K et al (2011) Spatial and temporal profiles of growth factor expression during CNS demyelination reveal the dynamics of repair priming. PLoS One 6(7):e22623CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Schulz K, Kroner A, David S (2012) Iron efflux from astrocytes plays a role in remyelination. J Neurosci 32:4841–4847CrossRefPubMedGoogle Scholar
  20. 20.
    Fischer R, Wajant H, Kontermann R, Pfizenmaier K, Maier O (2014) Astrocyte-specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor. Glia 62:272–283CrossRefPubMedGoogle Scholar
  21. 21.
    Connor JR, Pavlick G, Karli D, Menzies SL, Palmer C (1995) A histochemical study of iron-positive cells in the developing rat brain. J Comp Neurol 355:111–123CrossRefPubMedGoogle Scholar
  22. 22.
    Cheepsunthorn P, Palmer C, Connor JR (1998) Cellular distribution of ferritin subunits in postnatal rat brain. J Comp Neurol 400:73–86CrossRefPubMedGoogle Scholar
  23. 23.
    Franco PG, Pasquini LA, Pérez MJ, Rosato-Siri MV, Silvestroff L, Pasquini JM (2015) Paving the way for adequate myelination: the contribution of galectin-3, transferrin and iron. FEBS Lett 589:3388–3395CrossRefPubMedGoogle Scholar
  24. 24.
    McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85:890–802CrossRefPubMedGoogle Scholar
  25. 25.
    Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jiang P, Chen C, Wang R, Chechneva OV, Chung SH, Rao MS, Pleasure DE, Liu Y et al (2013) hESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury. Nat Commun 4:2196PubMedPubMedCentralGoogle Scholar
  27. 27.
    Valeiras B, Rosato-Siri MV, Codagnone M, Reines A, Pasquini JM (2014) Gender influence on schizophrenia-relevant abnormalities in a cuprizone demyelination model. Glia 62:1629–1644CrossRefPubMedGoogle Scholar
  28. 28.
    Kiernan JA, Chromoxane cyanine R. I (1984) Physical and chemical properties of the dye and of some of its iron complexes. J Microsc 134:13–23CrossRefPubMedGoogle Scholar
  29. 29.
    Mirro J, Stass SA (1985) Fluorescent microsphere detection of surface antigens and simultaneous cytochemistries in individual hematopoietic cells. Am J Clin Pathol 83:7–11CrossRefPubMedGoogle Scholar
  30. 30.
    Rosato Siri MV, Badaracco ME, Pasquini JM (2013) Glatiramer promotes oligodendroglial cell maturation in a cuprizone-induced demyelination model. Neurochem Int 63:10–24CrossRefPubMedGoogle Scholar
  31. 31.
    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:2002–2007CrossRefGoogle Scholar
  32. 32.
    Rajasekharan S, Baker KA, Horn KE, Jarjour AA, Antel JP, Kennedy TE (2009) Netrin 1 and dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA. Development 136:415–426CrossRefPubMedGoogle Scholar
  33. 33.
    Ferreira T, Blackman A, Oyrer J, Jayabal A, Chung A, Watt A, Sjöström J, van Meyel D (2014) Neuronal morphometry directly from bitmap images. Nat Methods 11:982–984CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P et al (2014) An RNA-sequencing Transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. The J of Neurosc 34:11929–11947CrossRefGoogle Scholar
  35. 35.
    Crain JM, Nikodemova M, Watters JJ (2013) Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res 91(9):1143--1151Google Scholar
  36. 36.
    Nualart-Marti A, Solsona C, Douglas FR (2013) Gap junction communication in myelinating glia. Review. Biochim and Biophys Acta 1828:69–78CrossRefGoogle Scholar
  37. 37.
    Kwik-Uribe CL, Golub MS, Keen CL (2000) Chronic marginal iron intakes during early development in mice alter brain iron concentrations and behavior despite postnatal iron supplementation. J Nutr 130:2040–2048CrossRefPubMedGoogle Scholar
  38. 38.
    Lozoff B (2000) Perinatal iron deficiency and the developing brain. Pediatr Res 48:137–139CrossRefPubMedGoogle Scholar
  39. 39.
    Ortiz E, Pasquini JM, Thompson K, Felt B, Butkus G, Beard J, Connor JR (2004) Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J Neurosc Res 77:681–689CrossRefGoogle Scholar
  40. 40.
    Rao R, Tkac I, Unger EL, Ennis K, Hurst A, Schallert T, Connor J, Felt B et al (2013) The iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of frontal cortex and hippocampus in adult rats. Pediatr Res 73:31–37CrossRefPubMedGoogle Scholar
  41. 41.
    Lozoff B, Georgieff MK (2006) Iron deficiency and brain development. Semin Pediatr Neurol 13:158–165CrossRefPubMedGoogle Scholar
  42. 42.
    Georgieff MK (2008) The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus. Biochem Soc Trans 36:1267–1271CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Greminger AR, Mayer-Pröschel M (2015) Identifying the threshold of iron deficiency in the central nervous system of the rat by the auditory brainstem response. ASN Neuro 7:1–10CrossRefGoogle Scholar
  44. 44.
    Harvey L, BoksaP (2014) Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring. Brain Behav Immun 40:27–37CrossRefPubMedGoogle Scholar
  45. 45.
    Badaracco ME, Siri MV, Pasquini JM (2010) Oligodendrogenesis: the role of iron. Biofactors 36:98–102PubMedGoogle Scholar
  46. 46.
    Morath DJ, Mayer-Proschel M (2002) Iron deficiency during embryogenesis and consequences for oligodendrocyte generation in vivo. Dev Neurosci 24:197–107CrossRefPubMedGoogle Scholar
  47. 47.
    Stefanović D, Stefanović M, Lalošević D (2015) Use of eriochrome cyanine R in routine histology and histopathology: is it time to say goodbye to hematoxylin? Biotech Histochem 90:461–469CrossRefPubMedGoogle Scholar
  48. 48.
    Noble M, Smith J, Power J, Mayer-Pröschel M (2003) Redox state as a central modulator of precursor cell function. Ann N Y Acad Sci 991:251–271CrossRefPubMedGoogle Scholar
  49. 49.
    Huang S, Du F, Li L, Liu Y, Liu Y, Zhang C, Qian ZM (2014) Angiotensin II inhibits uptake of transferrin-bound iron but not non-transferrin-bound iron by cultured astrocytes. Neuropeptides 48:161–166CrossRefPubMedGoogle Scholar
  50. 50.
    Simpson IA, Ponnuru P, Klinger ME, Myers RL, Devraj K, Coe CL, Lubach GR, Carruthers A et al (2015) A novel model for brain iron uptake: introducing the concept of regulation. J Cereb Blood Flow Metab 35:48–57CrossRefPubMedGoogle Scholar
  51. 51.
    Miyamoto N, Maki T, Shindo A, Liang AC, Maeda M, Egawa N, Itoh K, Lo EK et al (2015) Astrocytes promote Oligodendrogenesis after white matter damage via brain-derived Neurotrophic factor. J Neurosci 35:14002–14008CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Jeong SY, David S (2003) Glycosyl phosphatidyl inositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 278:27144–27148CrossRefPubMedGoogle Scholar
  53. 53.
    Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122CrossRefPubMedGoogle Scholar
  54. 54.
    Messersmith DJ, Murtie JC, Le TQ, Frost EE, Armstrong RC (2000) Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination. JNeurosci Res 62:241–256CrossRefGoogle Scholar
  55. 55.
    Hinks GL, Franklin RJ (1999) Distinctive patterns of PDGF-A, FGF-2, IGF-I, and TGF-beta1 gene expression during remyelination of experimentally-induced spinal cord demyelination. Mol Cell Neurosci 14:153–168CrossRefPubMedGoogle Scholar
  56. 56.
    Fernandez LL, de Lima MN, Scalco F, Vedana G, Miwa C, Hilbig A, Vianna M, Schröder N (2011) Early post-natal iron administration induces astroglial response in the brain of adult and aged rats. Neurotox Res 20:193–199CrossRefPubMedGoogle Scholar
  57. 57.
    Homkajorn B, Sims NR, Muyderman H (2010) Connexin 43 regulates astrocytic migration and proliferation in response to injury. Neurosci Lett 486:197–201CrossRefPubMedGoogle Scholar
  58. 58.
    Szajkowski R, Friel JK, Diehl-Jones W, Valdimarsson G (2006) Effects of iron and oxidative stress on Cx43 expression and phosphorylation. FASEB J 20:A617Google Scholar
  59. 59.
    Mairuae N, Connor JR, Cheepsunthorn P (2011) Increased cellular iron levels affect matrix metalloproteinase expression and phagocytosis in activated microglia. Neurosci Lett 500:36–40CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang X-Y, Cao J-B, Zhang L-M, Li Y-F, Mi W-D (2015) Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice. J Neuroinflammation 12:20CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Rogers JT (1996) Ferritin translation by interleukin-1and interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes. Blood 87:2525–2537PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Maria Victoria Rosato-Siri
    • 1
  • Leandro Marziali
    • 1
  • María Eugenia Guitart
    • 1
  • Maria Elvira Badaracco
    • 1
  • Mariana Puntel
    • 2
  • Fernando Pitossi
    • 2
  • Jorge Correale
    • 3
  • Juana Maria Pasquini
    • 1
  1. 1.Departamento de Química Biológica, Facultad de Farmacia y Bioquímica. IQUIFIB-CONICETUniversidad de Buenos AiresBuenos AiresArgentina
  2. 2.Instituto Leloir - IIBBA-CONICETBuenos AiresArgentina
  3. 3.Instituto de Investigaciones Neurológicas Dr. Raúl Carrea, FLENIBuenos AiresArgentina

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