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Author:

Halfpenny, Christopher Andrew

Title:

Remyelination biology : the neurobiology of oligodendrocyte progenitor cells and their

potential for myelin repair in multiple sclerosis

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Remyelination Biology The Neurobiology of Oligodendrocyte Progenitor Cells and Their Potential for Myelin Repair in Multiple Sclerosis Christopher Andrew Halfpenny BSc MBBS MRCP Uni\\.~rsity A dissertation submitted to the of Bristol in accordance with the requirements of the degree of Doctor of Philosophy in the Faculty of Medicine.

December 2003 \\'ord Count 44.7t)5 Remyelination Biology 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 the

–  –  –

morphology 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.

–  –  –

I would like to dedicate this to my beloved wife Sue and to my wonderful children Will and Emmie. They have supported me with loye, encouraged me to persevere and have born my absence with patience. They have refreshed me with their fun, and continue to give me inexpressible joy. Above all they have reminded me that the Lord is sovereign over all things, He created the biology that I have been inYestigating, and it is only through His strength that I have been able to do this work. Mayall that I have achieved be for His greater glory!

I would like to acknowledge the enormous support I have received from my supervisor, Prof. Neil Scolding. He has been generous with his time and resources, patient with my shortcomings and approachable throughout. He has guided, encouraged and corrected my work with diligence and wisdom and has been a role model and mentor, both as a compassionate, skilled and learned clinician and an eminent scientist.

I would also like to acknowledge the help of Sarah Stevens, and Dr Heather Wilson who gave me instruction in cell culture techniques and Sarah also for her valued advice in setting up the laboratory in Bristol. I would like to thank Vivien Down for her technical and moral support, as well as many others who have assisted in the Glial Cell Biology Laboratories. I would like to acknowledge the support of Prof. David Wraith and his staff at the Department of Pathology, and Dr John Crang of Cambridge University for help in setting up the magnetic bead separation. I would also like to acknowedge the assistance of the cytogenetic department of the Lewis Laboratories for karyotyping HW 1&2.

Finally I would like to thank my parents, parents-in-law, family and friends for their love, support, encouragement, humour and wisdom.

Rem)elination Biology

DECLARATIO~ AUTHOR'S

I declare that the work in this dissertation was carried out in accordance with the Regulations of the University of Bristol. The work is original except where indicated by special reference in the text and no part of the dissertation has been submitted for any other degree. Chapter 6 has been published (Halfpenny & Scolding 2003) and was co-authored by Prof. NJ.Scolding who supervised this work, and some of the text has been reproduced from tracts written predominantly by the author, but published with co-authors ProfNJ.Scolding and Dr T.M.Benn (Halfpenny et al. 2002). It is reproduced here with some minor changes. Any views expressed in the dissertation are those of the author and in no way represent those of the University of Bristol. The dissertation has not been presented to any other University for examination either in the United Kingdom or overseas.

–  –  –

Multiple Sclerosis Multiple Sclerosis (MS) is the commonest progressive neurological condition affecting young people in Britain. It affects some 55,000 people in this country alone.

It has devastating consequences to the patients, and far-reaching social and economic sequelae. Despite much publicity, the treatments available are disappointing, expensive and ultimately fail to reverse or halt the disease.

The disease is typified by episodes of discrete neurological deficits progressing over days and resolving, often completely, over weeks. They characteristically affect different parts of the central nervous system (CNS) at different times, but certain regions appear particularly susceptible. Common manifestations include unilateral visual loss from optic neuritis, ataxia and diplopia from brainstem lesions and sensorimotor symptoms from spinal cord involvement. These neurological episodes are irregular, but typically occur slightly less than once a year (Compston & McAlpine 1998) (relapsing-remitting phase).

However, with time, previously dramatic recovery from attacks becomes less complete, and disability accumulates (secondary progressive phase). Relapses may become less frequent or cease altogether. Spasticity, disabling ataxia and sphincter disturbance are common accompaniments of chronic disease. A proportion of patients (300/0) develop progressive disease from the outset, and one-third of these never manifest acute relapses (Weinshenker et al. 1989) (primary progressive mUltiple sclerosis).

The majority of research into MS has been aimed, directly or indirectly, at finding ways of controlling disease activity, and hence preventing progression. Though selfevidently wholly necessary, this approach ignores the disability already suffered by many.

Aetiology and pathology Despite a century and a hairs interest and enomlOUS investment in ~1S research. no causal hypothesis has been universally accepted. Controversies abound, as is amply demonstrated by the extraordinarily diverse hypotheses and counter-hypotheses currently proposed (Behan et al. 2002;Compston & McAlpine 1998J1awkes 2002).

Pn~e 13 Remyelination Biolog)

While many aspects of the disease do remain frustratingly elusive, painstaking research has provided a broadly coherent picture of disease pathogenesis, which requires a brief summary.

Important evidence comes from epidemiological studies. These reveal a complex interplay between genetic susceptibility and environmental triggers. The genetic contribution has been systematically explored; some 5-7 regions of the human genome are consistently identified, but none of these appear to carry alleles that are either sufficient or necessary for development of the disease (Compston 1999). However, consistent associations with the regions encoding the HLA complex and cytokine (TNFa) genes are important evidence for an immunological component to disease aetiology. The unusual epidemiology of the disease, and in particular the marked geographical variation and existence of restricted outbreaks (eg Faeroe Islands), implicate environmental agents, of which viruses have always been prime contenders.

However, while a clear relationship between relapse and viral infection has been established (Sibley et al. 1985), and many viruses have been proposed as contenders, no viral agent has ever been convincingly demonstrated as a cause for the disease.

Further important clues come from detailed pathological studies. Charcot described the essential pathological features of MS in the nineteenth century (Charcot 1868), and his observations have been confirmed and extended several times since. The classical pathological hallmarks of the disease are of areas of inflammation (plaques), often localised around blood vessels, in the brain and spinal cord. These contain prominent myelin destruction and oligodendrocyte death, with relative, but not absolute, preservation ofaxons. More recently it has been recognised that there are widespread abnormalities, including diffuse inflammation, small foci of demyelination (Allen & McKeown 1979) and axonal changes (Trapp et al. 1998) in macroscopically normal appearing white and grey matter as well.

While these three cardinal features of MS; inflammation, myelin loss, and relative axonal sparing, are present in all patients, there are sufficient differences between individuals to suggest that the pathogenic mechanisms may not be entirely uniform between MS patients. A study of actiyc demyelinating lesions in a large series of \1S patients found evidence for four di tTcrcnt pattenls of pathological findings that were conserved within lesions from the same patient. The most conunon pattern (designated pattern II). found in just oyer half of these patients. suggested myelin dalllage

Page 14 Remyelination Biology



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