Tuesday, 15 November 2011

A new type of cell supports remyelination


Background: In MS, oligodendrocyte precursor cells (OPCs), the cells that produce oligodendrcytes - which in turn make myelin - attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the MS lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia, an immune cell of the central nervous system, are known to play a central role in neuroinflammatory processes. 

Fig: Microglia stained using the silver method.
Aim: To investigate the microglia that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum (an important tract of fibres linking the two hemispheres of the brain) during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. 

Results: The investigators provide evidence for the existence of a specific subtype microglia that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis (ingestion) of myelin debris (damage myelin) and apoptotic cells (dead cells) during demyelination. Furthermore, they express a cytokine and chemokine repertoire (immune signalling molecules) enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support (growth factors) during remyelination. 

Conclusions: This study not only provides a detailed transcriptomic (gene product) analysis of the remyelination-supportive microglia type but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis (keeping the tissue healthy and in balance) and the support of regeneration already at the earliest stages in the development of demyelinating lesions. 

"This is a basic science experiment looking at the contribution of a specific cell in promoting remyelination. Is it important? Yes, I think so. If we can show that the same cells exist in humans and we can work-out how to stimulate these cells and enhance their function we may have a treatment that promotes remyelination. Experts in the field believe that remyelination is the best form of neuroprotection we have; if an axon or nerve fibre is demyelinated for too long it is destined to die. This is why we are desperate to get drugs that can protect the nerves from dying so remyelination can occur or to remyelinate them as soon as possible to stop them dying." 

"This study demonstrates why we need to invest in basic science; insights from basic biology underpins our understanding of biology and disease and eventually leads to the design of rational treatments."


CoI: Prof. Sandra Amor (2nd author) is a member of our group

14 comments:

  1. Prof G, once a nerve dies, does that meant it's dead forever? Like, let's say you remyelinate a dead axon, will that dead axon come back to life?

    I'm interested because I know if remyelination therapy one day becomes a reality, many of us may be beyond help because our axons might be dead.

    Also, I think you once said that perhaps Fingolimod may be able encourage remyelination in PPMS'ers. Are you still hopeful about this theory and why are you so confident in the remyelination potential of Fingolimod in PPMS'ers?

    Lastly, is the experimental remyelination work of Prof Robin Franklin at Cambridge Uni different to the study you're discussing in this specific post?

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  2. I didn't know that Fingolimod can aid PPMS'ers. Is this true? Why doesn't my consultant prescribe it to me then?

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  3. Re: "Once a nerve dies, does that meant it's dead forever? Like, let's say you remyelinate a dead axon, will that dead axon come back to life?"

    Once a nerve dies it is dead and all it processes that include the axons.

    Many nerves have multiple axonal branches and damage to one does not necessarily result in it dying. If the cell body survives axons, can in theory, regrow.

    Axons that are demyelinated are at risk dying, this is why remyelinating them ASAP is important to prevent from dying.

    If enough of the axon(s) are damaged it can lead to the nerve body or nerve cell dying.

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  4. Re: "Once a nerve dies, does that meant it's dead forever? Like, let's say you remyelinate a dead axon, will that dead axon come back to life?"

    Once a nerve dies it is dead and all it processes that include the axons.

    Many nerves have multiple axonal branches and damage to one does not necessarily result in it dying. If the cell body survives axons, can in theory, regrow.

    Axons that are demyelinated are at risk dying, this is why remyelinating them ASAP is important to prevent from dying.

    If enough of the axon(s) are damaged it can lead to the nerve body or nerve cell dying.

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  5. Re: "I think you once said that perhaps Fingolimod may be able encourage remyelination in PPMS'ers."

    There is some basic science data that suggests fingolimod may encourage remyelination. This is why Novartis are currently running a clinical trial to see if it works in PPMS.

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  6. Re: "I didn't know that Fingolimod can aid PPMS'ers."

    We are not sure about this; we need to wait for the results of the PPMS fingolimod trial.

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  7. When a nerve dies, does it physically disappear, do its constituents get somehow reabsorbed in to the surrounding tissues? I have wondered about this for a while, wondering whether, if remyelin becomes a treatment, there will still be axons left to be remyelinated. I hope you can undertand my questions which could be put more coherently!

    This does sound exciting.

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  8. Could you tell us something about the role of pericytes in MS? Do they interact with the damage-causing agents or get involved solely with the restoration process afterwards?

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  9. Pericytes are cells that are just outside the blood vessel but are within the glia limitans so they are not in the brain parencymal tissue.
    Some people think they are smooth muscle related other including me see then as perivascular (around the blood vessel) microglia. So I suspect that they are more involved in triggering damaging cells that enter via the blood.
    But I don't really know the answer.

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  10. I'm curious as to know what the fingolimod trials for PPMS aim to achieve? How does this drug work and how will it be of benefit to those with PPMS when everyting else has failed?

    Also, what do you mean by 'basic science data'? What is 'basic' about the data?

    Futhermore, when will the trials for fingolimod in PPMS prove conclusive?

    I really like your blog guys. Thank you so much for sticking with it.

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  11. Fingolimod is an Spingosine-1-phosphate receptor modulator and blocks white blood cell activity by the S1P1 receptor and stops relapses. If the drug is just immunosuppressive there is a chance of failure because drugs need to do things other than just that.

    However, tt can also affect glial cells within the brain. There is some evidence that myelin forming cells can be influenced by fingolimod, notably by the S1P5 receptor and may facilitate some recovery of nerve function (some of this research from Team G).

    Probably Novartis hopes it causes remyelination which we think will be good for slowing progressive MS, but it could influence B cell function as another possible target or could do something that we do not even understand yet.

    In my opinion to date there is no really good evidence that it does actually promote remyelination and in some of our work in experimental models there was progression despite treatment.

    However I believe that a significant proportion of PP MSers do benefit from immunosuppressive agents and I really think it will be good for some people even if not all. If it does other stuff..let us hope.

    The jury is out and we will have to wait and see what really happens. I have my thoughts we will see!

    Trials are ongoing see
    clinicaltrials.gov NCT00731692 for details and are due to complete in 2014. Prof G maybe able to fill you in more

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  12. "Also, what do you mean by 'basic science data'? What is 'basic' about the data?"

    OK fair point. It is a sort of definition about they type of work that scientists do and has nothing to do with the literal meaning of the words

    The stuff that prof G typical does is called "clinical science" because it involves doing work with people in the clinic with disease.

    The stuff that Mouse Doc does is called "basic science" because it is not "clinical science".....cos so called "real" doctors are snobs.

    In fact the stuff of "basic science" is far from basic and involves some of the most innovative and exciting ideas on the planet.

    It is the stuff that gives the the tools for the "clinical scientists" to work with, who in fact do the basic stuff as most of the hard stuff of invention has been done long before they get their hands on the drugs that they test.

    The "basic" science can be often be seen as esoteric But who knows where it will lead? Who would have thought that studying bacteria that live in volcanic pools would have given us the tool that allowed the human genome to unravelled.

    Sometimes the science is called "applied" as it has direct relevance to a clinical application such as drug development.

    Hope that clears this terminology up

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  13. This is why I love this blog. Where else can you get that kind of analysis and breakdown other than by coming here? Thank you for that explanation MouseDoc. Although I wasn’t the person that posed the original question on figolimod, I am grateful for the informative reply. It’s stuff like this that allows us all to be expert patients.

    I had no idea about the differences between ‘basic, ‘clinical’ and ‘applied’ science. I guess that the stuff you’re doing is far from basic.

    I would like to know if fingolimod doesn’t prove efficacious in promoting remyelination, but has some other indefinable benefits for PPMS’ers, do you think that NICE will bother to licence it considering the huge costs involved and lack of measurable remyelinateive (not sure that is an actual word) clinical benefit? PPMS is apparently more of an orphan disease, therefore what do you look for when trialling drugs to try and treat it?

    This is fingolimod project an exciting prospect; though I take it that fingolimod isn’t the only novel therapy being trialled for PPMS? I too hope that the research leads to something positive in the coming few years. PPMS patients like us have been almost felt neglected for the last few decades. I hope there is a real sense of change about to take place.

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  14. "what do you look for when trialling drugs to try and treat it?"

    We are in still working out how best to show a drug is working in PPMS and how best to design the trials, see prof G's video on lumbar punctures.

    However at the end of the day we want to see a clinical benefit so stopping or slowing down the rate of progression is what we want to see. Then repair, and an improvement.

    If fingolimod works we would hope that NICE would approve, it but they haven't been so NICE with regard approving it for RR MS. It is only a matter of time I hope.

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