Biomedical subjects

Charles Ffrench-Constant

Publications and source records attributed to Charles Ffrench-Constant.

8 recordsLinked to original sources

PubMed2006

Beta1-integrin signaling mediates premyelinating oligodendrocyte survival but is not required for CNS myelination and remyelination.

Previous reports, including transplantation experiments using dominant-negative inhibition of beta1-integrin signaling in oligodendrocyte progenitor cells, suggested that beta1-integrin signaling is required for myelination. Here, we test this hypothesis using conditional ablation of the beta1-integrin gene in oligodendroglial cells during the development of the CNS. This approach allowed us to study oligodendroglial beta1-integrin signaling in the physiological environment of the CNS, circumventing the potential drawbacks of a dominant-negative approach. We found that beta1-integrin signaling has a much more limited role than previously expected. Although it was involved in stage-specific oligodendrocyte cell survival, beta1-integrin signaling was not required for axon ensheathment and myelination per se. We also found that, in the spinal cord, remyelination occurred normally in the absence of beta1-integrin. We conclude that, although beta1-integrin may still contribute to other aspects of oligodendrocyte biology, it is not essential for myelination and remyelination in the CNS.

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PubMed2006

Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells.

Inflammation associated with CNS demyelination provides an important stimulus for the activation of endogenous oligodendrocyte precursor cells (OPCs) and subsequent remyelination. This view is largely based on "loss-of-function" studies, whereby remyelination is impaired following depletion of inflammatory cells or mediators. However, "gain-of-function" approaches, asking whether inflammation directly enhances remyelination, have received less attention. We have addressed this issue using a model in which OPCs transplanted into the adult rat retina myelinate retinal ganglion cell axons around the point of injection. Inflammation (characterized by increased expression of the macrophage marker ED1 and the astrocyte marker GFAP, and the up-regulation of multiple cytokines) was induced in the retina by the administration of the TLR-2 ligand zymosan. Myelination, revealed by MBP+ myelin sheaths, was substantially increased when OPCs were injected into the inflamed retina compared to that achieved following transplantation into the normal, noninflamed retina. Our results have important implications for the development of immunomodulatory treatments for acute demyelinating disease and for the therapeutic creation of proremyelination environments in chronic demyelinating disease.

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PubMed2005

Dynamic regulation of integrin activation by intracellular and extracellular signals controls oligodendrocyte morphology.

BACKGROUND: Myelination requires precise control of oligodendrocyte morphology and myelin generation at each of the axons contacted by an individual cell. This control must involve the integration of extracellular cues, such as those on the axon surface, with intrinsic developmental programmes. We asked whether integrins represent one class of oligodendrocyte cell-surface receptors able to provide this integration. RESULTS: Integrins signal via a process of activation, a conformational change that can be induced either by "outside-in" signals comprising physiological extracellular matrix ligands (mimicked by the pharmacological use of the divalent cation manganese) or "inside-out" signalling molecules such as R-Ras. Increasing levels of outside-in signalling via the laminin receptor alpha6beta1 integrin were found to promote oligodendrocyte processing and myelin sheet formation in culture. Similar results were obtained when inside-out signalling was increased by the expression of a constitutively-active R-Ras. Inhibiting inside-out signalling by using dominant-negative R-Ras reduces processes and myelin sheets; importantly, this can be partially rescued by the co-stimulation of outside-in signalling using manganese. CONCLUSION: The balance of the equilibrium between active and inactive integrins regulates oligodendrocyte morphology, which is itself regulated by extrinsic and intrinsic cues so providing a mechanism of signal integration. As laminins capable of providing outside-in signals are present on axons at the time of myelination, a mechanism exists by which morphology and myelin generation might be regulated independently in each oligodendrocyte process.

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PubMed2005

Enhancing central nervous system remyelination in multiple sclerosis.

Recent studies on adult neural stem cells and the developmental biology of myelination have generated the expectation that neural precursors can repair the damaged central nervous system of multiple sclerosis patients where the endogenous remyelination process has failed. As a result, many laboratories are engaged in translational studies in which the goal is to design ways to promote remyelination and repair. Here we raise issues highlighted by prior experimental and human work that should be considered lest these studies become "lost in translation."

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PubMed2005

Regulation of neural progenitor proliferation and survival by beta1 integrins.

Neural stem cells give rise to undifferentiated nestin-positive progenitors that undergo extensive cell division before differentiating into neuronal and glial cells. The precise control of this process is likely to be, at least in part, controlled by instructive cues originating from the extracellular environment. Some of these cues are interpreted by the integrin family of extracellular matrix receptors. Using neurosphere cell cultures as a model system, we show that beta1-integrin signalling plays a crucial role in the regulation of progenitor cell proliferation, survival and migration. Following conditional genetic ablation of the beta1-integrin allele, and consequent loss of beta1-integrin cell surface protein, mutant nestin-positive progenitor cells proliferate less and die in higher numbers than their wild-type counterparts. Mutant progenitor cell migration on different ECM substrates is also impaired. These effects can be partially compensated by the addition of exogenous growth factors. Thus, beta1-integrin signalling and growth factor signalling tightly interact to control the number and migratory capacity of nestin-positive progenitor cells.

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PubMed2005

Integrin-growth factor interactions as regulators of oligodendroglial development and function.

Central nervous system (CNS) development requires mechanisms for the regulation of cell number. Although growth factors are essential determinants of the proliferation and apoptosis that determine final numbers, the long-range nature of signals from diffusible growth factors makes them insufficient for the provision of the precise and localized signals required. Integration of integrin and growth factor receptor signaling in controlling cell behavior has been an important theme of research over the past several years. The focus of this review is on the mechanisms by which integrin-growth factor interactions regulate the development of oligodendrocytes and provide a mechanism for controlling, both in space and in time, oligodendrocyte numbers in the developing CNS.

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PubMed2004

CNS axons retain their competence for myelination throughout life.

An important question relevant to developing remyelination therapies is whether axons that remain without myelin sheaths after an episode of demyelination retain myelination competence. To resolve this, we have developed a model of transplantation into the nerve fibre layer of the adult rat retina, where the axons are unmyelinated. In the adult, these axons can be myelinated by transplantation of both the oligodendrocyte progenitor cells (OPCs) and an OPC line (CG4). The extent of myelination achieved following transplantation of OPCs is the same in young adult recipients (2 months old) as that which occurs in old adult recipients (12-18 months old), indicating that there are no changes in axons remaining unmyelinated for many months that would prevent effective remyelination. This finding suggests that chronically demyelinated regions of axons such as those in seen in multiple sclerosis are likely to remain competent to be remyelinated.

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PubMed2002

The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration.

Spinal cord oligodendrocytes originate in the ventricular zone and subsequently migrate to white matter, stop, proliferate, and differentiate. Here we demonstrate a role for the chemokine CXCL1 and its receptor CXCR2 in patterning the developing spinal cord. Signaling through CXCR2, CXCL1 inhibited oligodendrocyte precursor migration. The migrational arrest was rapid, reversible, concentration dependent, and reflected enhanced cell/substrate interactions. White matter expression of CXCL1 was temporo-spatially regulated. Developing CXCR2 null spinal cords contained reduced oligodendrocytes, abnormally concentrated at the periphery. In slice preparations, CXCL1 inhibited embryonic oligodendrocyte precursor migration, and widespread dispersal of postnatal precursors occurred in the absence of CXCR2 signaling. These data suggest that population of presumptive white matter by oligodendrocyte precursors is dependent on localized expression of CXCL1.

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