Publications by authors named "William F Blakemore"

7 Publications

  • Page 1 of 1

Environmental signals regulate lineage choice and temporal maturation of neural stem cells from human embryonic stem cells.

Brain 2007 May;130(Pt 5):1263-75

Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Human embryonic stem cells (hESCs) are a potential source of defined tissue for cell-based therapies in regenerative neurology. In order for this potential to be realized, there is a need for the evaluation of the behaviour of human embryonic stem cell-derived neural stem cells (hES-NSCs) both in the normal and the injured CNS. Using normal tissue and two experimental models, we examined the response of clinically compatible hES-NSCs to physiological and pathological signals. We demonstrate that the phenotypic potential of a multipotent population of hES-NSCs is influenced by these cues both in vitro and in vivo. hES-NSCs display a temporal profile of neurogenic and gliogenic differentiation, with the generation of mature neurons and glia over 4 weeks in vitro, and 20 weeks in the uninjured rodent brain. However, transplantation into the pathological CNS accelerates maturation and polarizes hES-NSC differentiation potential. This study highlights the role of environmental signals in determining both lineage commitment and temporal maturation of human neural stem cells. Controlled manipulation of environmental signals appropriate to the pathological specificity of the targeted disease will be necessary in the design of therapeutic stem cell-based strategies.
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http://dx.doi.org/10.1093/brain/awm070DOI Listing
May 2007

A different regional response by mouse oligodendrocyte progenitor cells (OPCs) to high-dose X-irradiation has consequences for repopulating OPC-depleted normal tissue.

Eur J Neurosci 2007 Jan;25(2):417-24

MS Society Cambridge Centre for Myelin Repair and the Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK.

This study was designed to investigate whether the residual, dysfunctional oligodendrocyte progenitor cells (OPCs) observed following X-irradiation of the mouse spinal cord [D. M. Chari et al. (2003) Exp. Neurol., 198, 145-153], the presence of which prevented the endogenous repopulation of these areas from normal tissue, reflects a general response of OPCs in the mouse central nervous system (CNS) to X-irradiation. The brains of adult mice were exposed to 40 Gy of X-irradiation and the effect of X-irradiation on the OPCs was assessed up to 4 weeks post-irradiation using anti-NG2 antibodies. X-irradiation resulted in almost complete depletion of OPCs within the telencephalon (cortex, corpus callosum and hippocampus) by 7 days post-irradiation, which was followed by progressive repopulation of OPCs from non-irradiated areas of the cortex. By contrast, within the lower brain centres (the diencephalon and mesencephalon) OPC loss occurred much more slowly so that 26% of the OPCs still remained 4 weeks after X-irradiation. The consequence of this heterogeneous response to X-irradiation was that whereas transplanted and endogenous OPCs rapidly established themselves in the OPC-depleted telencephalon this did not occur in the areas where there was incomplete depletion of endogenous OPCs. Our findings confirm not only the requirement for almost complete OPC depletion in order to establish transplanted OPCs in normal tissue but also highlight a heterogeneity of progenitor populations in different areas of the mouse CNS.
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http://dx.doi.org/10.1111/j.1460-9568.2007.05313.xDOI Listing
January 2007

Corticosteroids delay remyelination of experimental demyelination in the rodent central nervous system.

J Neurosci Res 2006 Mar;83(4):594-605

Cambridge Centre for Brain Repair and Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

High dose corticosteroid (CS) administration is a common mode of therapy in treatment of acute relapses in multiple sclerosis (MS) but the effects of CS on remyelination and the cellular mechanisms mediating this repair process are controversial. We have examined CS effects on repair of toxin-induced demyelinating lesions in the adult rat spinal cord. Corticosteroids reduced the extent of oligodendrocyte remyelination at 1 month post lesion (whereas Schwann-cell mediated repair was unaffected). However, CS did not cause permanent impairment of remyelination as lesions were fully remyelinated at 2 months after cessation of treatment. The delay in oligodendrocyte mediated repair could be attributed to inhibition of differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes, with no effect of CS treatment observed on OPC colonisation of the lesions. No differences were observed in animals treated with methylprednisolone succinate alone or with a subsequent prednisone taper indicating that CS effects occur at an early stage of repair. The potential consequences of delayed remyelination in inflammatory lesions are discussed.
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http://dx.doi.org/10.1002/jnr.20763DOI Listing
March 2006

Oligodendrocyte progenitor cell (OPC) transplantation is unlikely to offer a means of preventing X-irradiation induced damage in the CNS.

Exp Neurol 2006 Mar 10;198(1):145-53. Epub 2006 Jan 10.

Cambridge Centre for Brain Repair and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.

Oligodendrocyte lineage cells [oligodendrocytes and their parent cells, the oligodendrocyte progenitor cells (OPCs)] are depleted by X-irradiation and progenitor cell transplantation has been proposed as a therapeutic strategy to counteract radiation induced myelopathy. Previous studies have demonstrated that oligodendrocyte progenitor cell (OPC) depletion is a prerequisite for establishing transplanted OPCs in normal tissue. One can therefore predict that the extent and timing of OPC depletion and regeneration following X-irradiation will be crucial factors in determining the feasibility of this therapeutic approach. To address this issue, we have examined the time course of OPC depletion and regeneration following a range of X-irradiation doses (5 to 40 Gy), and its relationship to establishing transplanted OPCs in X-irradiated tissue. Doses above 10 Gy resulted in rapid death of OPCs. With doses up to 20 Gy, surviving X-irradiated OPCs were capable of robust regeneration, restoring normal densities within 6 weeks. Transplanted OPCs could only be established in tissue that had been exposed to > or =20 Gy. Since 20 Gy is close to the ED50 for radiation necrosis, our findings demonstrate the limitation of OPC replacement strategies.
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http://dx.doi.org/10.1016/j.expneurol.2005.11.023DOI Listing
March 2006

The presence of astrocytes in areas of demyelination influences remyelination following transplantation of oligodendrocyte progenitors.

Exp Neurol 2003 Dec;184(2):955-63

Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge CB3 OES, UK.

To date, most experiments examining the myelination potential of transplanted cells have been undertaken into either the immature nervous system or into acutely demyelinating lesions. Since these are situations where myelination or remyelination are occurring, such studies provide little information on the likely outcome of introducing myelinogenic cells into area of chronic demyelination. In an attempt to gain a greater understanding of the interaction between astrocytes and oligodendrocyte progenitors in areas of demyelination, we undertook transplantation experiments in which an identical preparation of oligodendrocyte progenitors (OPCs) was (1) transplanted directly into astrocyte-free areas of acute demyelination (3 days after induction), (2) transplanted cranial to similar areas of demyelination (20 days after induction) or (3) transplanted cranial to areas of demyelination (20 days after induction) that had been injected with astrocytes at 3 days to confront OPCs with demyelinated axons in an astrocytic environment. The acute astrocyte-free lesions were remyelinated by oligodendrocytes and Schwann cells while the delayed interaction of OPCs with demyelinating lesions resulted in only oligodendrocyte remyelination, the extent of which was reduced when the area of demyelination contained astrocytes. The results of these experiments illustrate that the introduction of OPCs into an astrocyte-free area of demyelination soon after its induction favours Schwann cell differentiation while the presence of established astrocytes in an area of demyelination has an inhibitory effect on the extent of oligodendrocyte remyelination achieved by OPCs.
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http://dx.doi.org/10.1016/S0014-4886(03)00347-9DOI Listing
December 2003

Oligodendrocyte progenitor cells in the adult rat CNS express myelin oligodendrocyte glycoprotein (MOG).

Brain Pathol 2002 Oct;12(4):463-71

Department of Veterinary Clinical Medicine, University of Cambridge, United Kingdom.

While the effects of high dose X-irradiation on mitotically active progenitor cells and remyelination are well-documented, its effects on myelinating oligodendrocytes are less clear, due in part to divergent views on their mitotic capacity. To examine the effect of X-irradiation on oligodendrocytes, the spinal cord of rats was exposed to 40 Gy of X-irradiation and the number of oligodendrocytes and oligodendrocyte progenitors in the dorsal funiculi at T12 and L1 was determined by in situ hybridization using cRNA-probes for platelet derived growth factor alpha receptor (PDGFRalpha) (to identify oligodendrocyte progenitors), exon 3b of proteolipid protein (PLP) (to identify mature oligodendrocytes) and myelin oligodendrocyte glycoprotein (MOG). X-irradiation resulted in no change in the number of PLP positive cells and no loss of myelin internodes, but caused an almost complete loss of PDGFRalpha-expressing cells, and a reduction in the number of MOG positive cells to a number similar to that found using the PLP exon 3b probe. Importantly, the number of radiation-sensitive MOG-expressing cells was similar to the number of PDGFRalpha positive cells. To determine if the radiation-sensitive MOG positive cells were the same population as the radiation sensitive PDGFRalpha-expressing cells, MOG and PDGFRalpha-expressing cells were isolated from the adult CNS using antibody coated magnetic beads. Twelve to thirteen percent of MOG positive cells were PDGFRalpha positive and nearly all the PDGFRa isolated cells were MOG and galactocerebroside positive. Double immunofluorescence revealed colocalization of NG2 and MOG on cells in the normal adult rat spinal cord. These results show that in situ in the adult rat spinal cord white matter oligodendrocyte progenitors are MOG positive and indicates that expression of MOG cannot be regarded a marker that only identifies mature myelin-supporting oligodendrocytes in tissue.
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http://dx.doi.org/10.1111/j.1750-3639.2002.tb00463.xDOI Listing
October 2002

Efficient recolonisation of progenitor-depleted areas of the CNS by adult oligodendrocyte progenitor cells.

Glia 2002 Mar;37(4):307-13

Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

A widely quoted hypothesis for the failure of remyelination in multiple sclerosis (MS) is the exhaustion of the oligodendrocyte progenitor cell (OPC) pool that is strongly implicated as the source of remyelinating oligodendrocytes in demyelinating lesions. Despite this, little is known about the responses of adult OPCs to adjacent areas of the CNS from which their numbers are depleted. We have developed an experimental model to study the pattern and rate of repopulation of OPC-depleted zones, by endogenous OPCs in the adult rat spinal cord. By X-irradiating short lengths of the spinal cord with 40 Gy of X-irradiation, we were able to produce a highly localised depletion of OPCs that allowed us to study the responses of cells located in adjacent normal areas, to this local depletion. Using both NG2 immunohistochemistry and PDGFalphaR in situ hybridisation to identify OPCs, we demonstrate that endogenous OPCs repopulated the depleted areas slowly, but completely. This repopulation occurred at the rate of approximately 0.5 mm/week in the first month. Most cells at the leading edge of repopulation had complex, branching morphologies. The repopulation process was capable of restoring the density of progenitors in repopulated areas to that of normal tissue and was not associated with a secondary progenitor loss in tissue from which progenitor cells were generated. These findings indicate that depletion of the OPC population around lesions is not likely to be the primary explanation for remyelination failure in MS.
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March 2002