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Robin J M Franklin

Publications and source records attributed to Robin J M Franklin.

13 recordsLinked to original sources
PubMed2003

Lentiviral vectors for gene delivery to normal and demyelinated white matter.

Lentiviral vectors are increasingly used for gene delivery to neurons and in experimental models of neurodegeneration. Their use in gene delivery to white matter and their potential value in preventing or repairing CNS demyelination has received less attention. Here we show using a VSV-G-pseudotyped HIV-derived vector expressing the marker gene LacZ that lentiviral vectors transduce the major macroglial cell types present in normal white matter (astrocytes, oligodendrocytes, and oligodendrocyte progenitors). Injection of lentiviral vectors causes an inflammatory response at the injection site characterized by OX42(+) and ED1(+) macrophages, but only a few CD8(+) and no CD4(+) lymphocytes, and mild demyelination. Injection of lentiviral vectors into areas of toxin-induced demyelination resulted in significant numbers of cells expressing the marker gene and was a more effective means of gene delivery than was a LacZ-expressing murine retroviral vector.

Animals↗
PubMed2003

Remyelination by transplanted olfactory ensheathing cells.

The olfactory ensheathing cells (OECs) of the peripheral olfactory system associate with the axons of the first cranial nerve. These axons are not myelinated by OECs because of their very small diameter. However, when OECs are transplanted into areas where they encounter larger-diameter axons, such as in a model of primary demyelination, these cells assume a myelinating phenotype. Myelinating OECs very closely resemble myelinating Schwann cells by all criteria currently examined, including morphology, ultrastructure, biochemistry, and transcriptional regulation. Indeed, it is currently impossible to reliably distinguish myelinating OECs and myelinating Schwann cells that have been transplanted into experimental models of CNS demyelination. This article describes recent studies on the myelinating properties of transplanted OECs, focusing on their intrinsic myelinating potential and how this can be augmented by the presence of meningeal cells. The relative merits of OECs compared with Schwann cells when transplanted into astrocyte-containing lesions in the CNS are discussed together with their potential role in transplanted-mediated repair of demyelinating disease such as multiple sclerosis.

Astrocytes↗
PubMed2003

Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells.

Olfactory ensheathing cells (OECs) are candidate cells for transplant-mediated repair of persistent demyelination in diseases such as multiple sclerosis. If this approach is to make the transition from laboratory to clinic, an important issue is the most suitable composition of the OEC transplant. Isolation of OECs involves concurrent isolation of other cell types, and specific selection techniques are required to produce purified OECs. In this study we address whether the purity of the OEC transplant affects their ability to remyelinate. Surprisingly, we find that a purified preparation of OECs, selected on the basis of low-affinity nerve growth factor receptor (p75) expression, results in less extensive remyelination than an unpurified preparation following transplantation into areas of persistent demyelination in rodent CNS in the X-irradiation/ethidium bromide (X-EB) model. A distinctive feature of the unpurified preparation both in vitro and following transplantation is the presence of meningeal cells. When meningeal cells are added to purified OECs there is a significant improvement in the extent of remyelination compared with the purified OECs, although if the cells are present in too great an abundance this beneficial effect is lost. These results highlight the important concept that the regenerative properties of OECs are profoundly influenced by the cells with which they are transplanted.

Animals↗
PubMed2003

Impaired remyelination and depletion of oligodendrocyte progenitors does not occur following repeated episodes of focal demyelination in the rat central nervous system.

It has been hypothesized that the progressive failure of remyelination in chronic multiple sclerosis is, in part, the consequence of repeated episodes of demyelination at the same site, eventually depleting oligodendrocyte progenitor cells (OPCs) and exhausting the remyelinating capacity. We investigated the effect of previous focal, ethidium bromide-induced demyelination of brain stem white matter (with intervening recovery) on the efficiency of the remyelination process during second and third subsequent episodes of demyelination, and the OPC response during a second episode of demyelination. Previous focal demyelinating lesions followed by recovery did not result in any retardation of the remyelination process, nor did they alter the proportion of Schwann cell versus oligodendrocyte remyelination. The OPC response during remyelination was quantified by in situ hybridization using a probe to platelet-derived growth factor-alpha receptor (PDGF alpha R), an OPC-expressed mRNA. Following recovery from focal, toxin-induced CNS demyelination, the OPC density returned to levels equivalent to those in normal white matter. Further more, there was no depletion of OPCs following repeated episodes of focal, toxin-induced CNS demyelination at the same site. These results indicate that repeated CNS demyelination, which has the opportunity to repair in the intervening period, is not characterized by impaired remyelination or depletion of OPCs.

Animals↗
PubMed2003

Quantifying the early stages of remyelination following cuprizone-induced demyelination.

The demyelinating toxin cuprizone is used increasingly in mouse studies of central nervous system remyelination. The value of this model for such studies depends on an accurate description of its quantifiable features. We therefore investigated histology and ultrastructure during the early oligodendrocyte differentiation phase of remyelination in mice given cuprizone and allowed to recover for 2 weeks. Limiting the dose of cuprizone to 0.2% overcame significant mouse morbidity and weight loss seen with a 0.4% dose, but the distribution of cuprizone-induced demyelination was anatomically variable. The caudal corpus callosum and dorsal hippocampal commissure mostly demyelinated at this dose, but the rostral corpus callosum and rostral cerebellar peduncles did not. This variable response, together with small axon diameters and hence thin myelin sheaths, hindered analysis of the progress of early remyelination. The proportion of myelinated and unmyelinated axons in defined regions followed expected trends, but there was pronounced variation between animals. Furthermore, group mean G ratios did not change as expected during the early stages of remyelination, and regression analysis revealed a complex relationship between axon diameter and myelin sheath thickness during this period. We also noted axonal pathology that persisted for at least 2 weeks after cuprizone withdrawal.

Animals↗
PubMed2002

Ageing and CNS remyelination.

Remyelination of demyelinated axons in the CNS is a regenerative process that, like many others, becomes less efficient with age. This article reviews a series of studies in which toxin models of demyelination have been used to characterize this phenomenon. The delayed rate of remyelination in older animals is associated with a decrease in the rate of oligodendrocyte progenitor recruitment and in the rate at which the recruited cells differentiate into remyelinating oligodendrocytes. The differences in the behaviour of oligodendrocyte lineage cells during remyelination in young and old animals are related to the age-related changes that occur in the expression of growth factors that affect the proliferation, migration and differentiation of oligodendrocyte progenitors, and in the inflammatory process associated with toxin-induced demyelination. Based on these differences, a conceptual framework is proposed to explain the age-associated effects on remyelination, which we have called the dysregulation hypothesis, and the feasibility of reversing these effects is discussed.

Aging↗
PubMed2002

The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation.

The age-associated decrease in the efficiency of CNS remyelination has clear implications for recovery from demyelinating diseases such as multiple sclerosis (MS) that may last for several decades. Developing strategies to reverse the age-associated decline requires the identification of how the regenerative process is impaired. We addressed whether remyelination becomes slower because of an impairment of recruitment of oligodendrocyte progenitors (OPs) or, as is the case in some MS lesions, an impairment of OP differentiation into remyelinating oligodendrocytes. The OP response during remyelination of focal, toxin-induced CNS demyelination in young and old rats was compared by in situ hybridization using probes to two OP-expressed mRNA species: platelet-derived growth factor-alpha receptor and the OP transcription factor myelin transcription factor 1 (MyT1). We found that the expression patterns for the two OP markers are very similar and reveal a delay in the colonization of the demyelinated focus with OPs in the old animals compared with the young animals. By comparing the mRNA expression pattern of MyT1 with that of the myelin proteins myelin basic protein and Gtx, we found that in the old animals there is also a delay in OP differentiation that increases with longer survival times. These results indicate that the age-associated decrease in remyelination efficiency occurs because of an impairment of OP recruitment and the subsequent differentiation of the OPs into remyelinating oligodendrocytes, and that strategies aimed at ameliorating the age-associated decline in remyelination efficiency will therefore need to promote both components of the regenerative process.

Age Factors↗
PubMed2002

Expression of the POU-domain transcription factors SCIP/Oct-6 and Brn-2 is associated with Schwann cell but not oligodendrocyte remyelination of the CNS.

The class III POU-domain transcription factor SCIP/Oct-6 is expressed by promyelinating Schwann cells and, in tissue culture, by oligodendrocyte progenitors (OPs), but is down-regulated in both cells types as they differentiate. Although the expression of SCIP/Oct-6 has been examined in peripheral nerve remyelination, its expression in CNS remyelination has not been addressed. Using a toxin model of demyelination, in which the demyelinated axons are remyelinated in an age-dependent manner by both oligodendrocytes and Schwann cells, we have compared the expression of SCIP/Oct-6 mRNA with that of an OP marker (PDGF-alphaR), a marker of myelinating oligodendrocytes (PLP), and markers of myelinating Schwann cells (P(0) and Krox-20) by in situ hybridization. We have found that the expression of SCIP/Oct-6 mRNA precedes that of P(0) and Krox-20 mRNA expression, but bears little correlation with the expression profiles of either PDGF-alphaR or PLP mRNA. Moreover, there is a spatial correlation between the expression SCIP/Oct-6 mRNA and that of P(0) but not of PDGF-alphaR. These results indicate that SCIP/Oct-6 expression following CNS demyelination is associated with Schwann cell and not oligodendrocyte remyelination. We have also shown that another POU-domain transcription factor, Brn-2, is expressed during CNS remyelination, but that like SCIP/Oct-6, it too has an expression profile indicating that it is associated with the Schwann cell component of remyelination. In addition, we show that Brn-2 expression in Schwann cells is not restricted to CNS remyelination but is also expressed in a similar manner to SCIP/Oct-6 during Schwann cell myelination of neonatal peripheral nerves and regenerating transected adult nerve and in cultured Schwann cells following induction of elevated cAMP levels.

Animals↗
PubMed2002

Remyelination of the demyelinated CNS: the case for and against transplantation of central, peripheral and olfactory glia.

Although originally developed as a research tool for studying glial-glial and glial-axonal interactions, the technique of transplanting glial cell into the central nervous system has more recently been employed as a potential means for repairing persistent demyelination in clinical disease. It has now been clearly established using various experimental models that oligodendrocyte lineage cells, Schwann cells and olfactory ensheathing cells can all produce new myelin sheaths around demyelinated or amyelinated axons following transplantation. However, this property alone does not necessarily mean that transplantation of these cells into demyelinated lesions in clinical disease will be successful. This article considers some of the properties that would be required of a transplanted myelinogenic cell and assesses the advantages and disadvantages of the currently available cell types.

Animals↗
PubMed2002

Why does remyelination fail in multiple sclerosis?

Multiple sclerosis is a common cause of neurological disability in young adults. The disease is complex -- its aetiology is multifactorial and largely unknown; its pathology is heterogeneous; and, clinically, it is difficult to diagnose, manage and treat. However, perhaps its most frustrating aspect is the inadequacy of the healing response of remyelination. This regenerative process generally occurs with great efficiency in experimental models, and sometimes proceeds to completion in multiple sclerosis. But as the disease progresses, the numbers of lesions in which demyelination persists increases, significantly contributing to clinical deterioration. Understanding why remyelination fails is crucial for devising effective methods by which to enhance it.

Animals↗
PubMed2002

Transplant mediated repair of the central nervous system: an imminent solution?

PURPOSE OF REVIEW: This article reviews recent advances in the use of cell transplantation to promote recovery from traumatic injury of the CNS, focusing on axonal regeneration in the spinal cord. RECENT FINDINGS: The significant recent findings reported are: (1) the increased expression of inhibitory chondroitin sulphate-proteoglycans in host tissue following Schwann cell transplantation, highlighting the effects the transplant may have on the ability of the host tissue to support regeneration; (2) the ability of embryonic and neural stem cells to promote recovery following transplantation into experimental models of spinal cord injury; (3) that delayed grafting for several weeks after transplantation does not diminish the graft effectiveness and may be advantageous; (4) the use of transplanted fibroblasts engineered to express neurotrophic genes in a conditionally regulated manner using tetracycline-inducible promoters; and (5) the initial reports on phase 1 clinical trials of foetal spinal cord grafts into patients with post-traumatic syringomyelia demonstrating their feasibility and safety. SUMMARY: Recent advances largely involve experimental refinements of existing approaches and the emergent application of stem cell biology to overcome spinal cord injury. While most experimental studies concentrate on single or restricted combinations of approaches, the most effective clinical strategies will be multi-component. Their formulation will require the development of intermediate models for bridging the differences between experimental models in laboratory animals and naturally occurring traumatic injury in humans.

Animals↗
PubMedDate not supplied

Recognition and diagnosis of lysosomal storage diseases in the cat and dog.

Lysosomal storage diseases are rare, inherited disorders caused by the deficiency of 1 or more enzymes within the lysosomes of cells or by the deficiency of an activating protein or cofactor necessary for enzyme activity. The enzyme deficiency leads to a catabolic blockade and subsequent accumulation of storage material, and this in turn leads, albeit indirectly, to a wide array of clinical signs. Many features of storage diseases make them difficult to recognize and diagnose. In this review, we summarize the clinical features of these diseases and outline the steps required to confirm a diagnosis.

Animals↗