Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409594
Title: Remyelination biology : the neurobiology of oligodendrocyte progenitor cells and their potential for myelin repair in multiple sclerosis
Author: Halfpenny, Christopher Andrew.
ISNI:       0000 0001 3524 4644
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2005
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Abstract:
Oligodendrocyte damage and myelin loss are cardinal features of Multiple Sclerosis (MS). Intrinsic myelin repair occurs in MS, mediated by quiescent oligodendrocyte progenitors that divide and migrate into demyelinated lesions. Experimental remyelination suggests that this repair restores function and can protect axons from subsequent degeneration. However this repair is limited, and disability supervenes. Designing treatments that augment myelin repair is both feasible and attractive. Much is known about the rodent oligodendrocyte lineage, but significant species differences exist and extrapolation to humans requires direct experimental support. Human oligodendrocyte progenitors are hard to grow in vitro, and supplies of source tissue and cellular yield are both limited. This problem is exacerbated by the failure of rodent mitogens to induce equivalent growth expansion of human progenitors. Several possible methods could be employed to circumvent these difficulties:- A conditionally immortalised human progenitor cell line transfected with a temperature sensitive oncogene has been reported. However, it was demonstrated that all stocks of this cell line have been irredeemably contaminated with rodent cells. It has been suggested that rodent progenitors can dedifferentiate into a more proliferative, multipotent phenotype. If dedifferentiation was a feasible method of inducing committed progenitors to a more proliferative state, it might be exoected that this property would be widespread amongst similar cells. The rodent progenitor cell line CG4 did not dedifferentiate in these circumstances, although the original experiment was not repeated. This exemplifies the problems of assessing lineage commitment using cell lines, while attesting to the stability of CG4. Primary cultures of glia from surgical specimens can yield small numbers of oligodendrocyte progenitors. Identifying these cells traditionally relies on themorphology and the expression of A285 antigens. Some studies have used NG2, an established marker of developing rodent progenitors but there is little experimental evidence to support its use in adult humans. It was shown that this antibody binds human endothelial cells, fibroblasts and certain types of astrocytes and thus lacks specificity for the oligodendrocyte lineage in vitro, although the proportion of cells staining with these markers requires further study. A population of bipolar and clawed cells, unidentified by traditional markers, appears to label with NG2. Purification of oligodendrocyte lineage cells using magnetic beads was optimised and there was preliminary evidence that the resulting cells proliferate in vitro. They gave rise to a population of small bipolar cells that were did not express A285 antigens but stained for NG2. We believe these to be of the oligodendrocyte lineage and further investigation of these cells is required. The emergent reports of stem cells in the adult mammalian brain were supported by studies using adult human tissue. These cells grow in aggregate cultures and can be induced to express oligodendrocyte markers. The feasibility of this approach as a source of oligodendrocyte lineage cells will rely on further work to ensure that their progeny remain faithful to native oligodendrocytes. Finally, rodent cells were used to establish that two key determinants of myelinating cell efficiency, migration and proliferation, are resistant to the effects anti-inflammatory drugs used in MS. It is anticipated that this type of research will soon be possible using human cells
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.409594  DOI: Not available
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