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The role of macrophages in the formation and repair of myelin

Copelman, Cheryl Amanda; (2000) The role of macrophages in the formation and repair of myelin. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Foetal rat brain aggregate cultures resemble the developing brain providing a unique system to investigate myelinogenesis, demyelination and repair. Supplementing aggregate cultures with macrophages accelerated cellular organisation and increased myelin deposition over time without affecting activity of the oligodendrocyte marker 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Pro-inflammatory cytokines and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies induced demyelination in myelinated aggregate cultures while oligodendrocytes were spared. Demyelination was associated with increased levels of a myelin basic protein (MBP) degradation peptide indicating proteolysis of myelin. MBP continued to accumulate following removal of demyelinating agents while peptide levels declined. Myelinogenesis in the aggregates was associated with patterns of growth factor mRNA expression comparable with those of the developing brain. The mRNA levels of platelet-derived growth factor-A (PDGF-A), a potent mitogen for oligodendrocyte progenitors, rose rapidly while fibroblast growth factor-2 (FGF-2) and ciliary neurotrophic factor (CNTF) mRNA increased gradually as MBP accumulated. The peak of transforming growth factor-β1 (TGF-β1) and neurotrophin-3 (NT-3) mRNA expression coincided with the appearance of MBP mRNA, while that of insulin-like growth factor-I (IGF-I) was more closely associated with the detection of MBP protein. Enhanced myelination in macrophage-enriched cultures was associated with reduced expression of CNTF and increased levels of TGF-β1 and FGF-2 mRNA both of which promote oligodendrocyte development in vitro. Demyelination induced a distinct pattern of expression of many myelination-associated growth factors. A rapid rise in CNTF mRNA in standard cultures closely followed by increases in FGF-2 and IGF-I was in contrast to the delayed induction of PDGF-A mRNA. In macrophage-enriched aggregates the rise in IGF-I mRNA following demyelination preceded that in standard cultures suggesting that macrophage- enrichment instigates a faster IGF-I response during remyelination. Since macrophage-rich demyelinating multiple sclerosis lesions also display signs of remyelination, macrophages, as a source of growth factors, have the potential to promote myelination and repair.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of macrophages in the formation and repair of myelin
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Demyelination
URI: https://discovery.ucl.ac.uk/id/eprint/10120974
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