Wednesday, 11 January 2012

Research: 2012 The Age of Repair

Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJ.Rejuvenation of regeneration in the aging central nervous system.Cell Stem Cell. 2012 ;10:96-103.

Remyelination is a regenerative process in the central nervous system (CNS) that produces new myelin sheaths from adult stem cells. The decline in remyelination that occurs with advancing age poses a significant barrier to therapy in the CNS, particularly for long-term demyelinating diseases such as
multiple sclerosis (MS). Here we show that remyelination of experimentally induced demyelination is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis. Restored remyelination in old animals involves recruitment to the repairing lesions of blood-derived monocytes from the young parabiotic partner, and preventing this recruitment partially inhibits rejuvenation of remyelination. These data suggest that enhanced remyelinating activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life.

Couldn't resist it.......The Franklinstein Mouse (with permission from House of Mouse)

We have commented on the important of age and remyelination before. It has been shown that in young mice that the default pathway following any insult that causes demyelination is repair and remyelination. However, it has been found that old mice do not repair that well.

As MSers accumulate more damage as the the disease progresses as you get older, then did this mean that the repair process fails because of age? Importantly is this is an irreversible process that time can not stop? The answer to this question is NO, you can still turn back the effects of age........We should have known this look at any aging star on the tele.

How did the do this?

Well they did this through parabiosis. Now we discussed the concept of parabiosis with you previously and in fact we talked about the ethics and the experimental design of the very same experiments as reported in this new article back in september, when you decided that the ends justify the means as far as your ethical use of animals go. So now you can see the actual results.

So in this paper they stiched the blood supply of two mice together to ask the question whether the failure of old mice to remyelinate is an intrinsic problem to old age or whether there is something in the the young mice that facilitated repair. In the previous studies we saw that there was a product in young blood that stimulated the growth of nerves. In this study the blood product that stimulated repair was the macrophages/monocytes (engulfing cells). The engulfing cells were the problem in old mice and if you could supply young monocytes then they can repair.

We know that these cells are vital in clearing up the debris after demyelination and without this repair does not occur. This means that if we find the trigger switches in monocytes then we have the potential to repair. So it is therefore interesting that we also reported some of work about a
macrophage type cell in the brain that promotes repair. So more pieces of the jigsaw on how to crack this remyelination problem are appearing all the time and with increasing this is good news.


  1. ‘Copaxone appears to repair nerve tissue in MS patients’

    Dr Robert Zivadinov at Buffalo has just completed a study (funded by Teva) suggesting Copaxone may have the potential to aid remyelination.

    “The researchers found that multiple sclerosis patients treated with Copaxone experienced significantly increased magnetization transfer ratio (MTR) - a nonconventional MRI technique used to investigate abnormalities in brain structures, and increased values indicate potential remyelination (re-generation of the nerve's myelin sheath) and axonal tissue repair in the patients' brains.

    Teva added that this was the first study to evaluate multiple sclerosis lesions as potential evidence for remyelination in patients treated with Copaxone.”

    Is this new?
    Is this interesting??

  2. What a great way to begin the New Year. This is such an optimistic post, and highly important to readers with long-term and progressive forms of multiple sclerosis. Your post is brimming with confidence and hope about being able to repair the CNS even after years of sustained damage and attacks. This is priceless news and I hope your convictions prove correct, preferably sooner rather than later.

    I read an article on last year which discussed whether emerging therapies to restore lost function will only benefit patients in the early phases of progressive degeneration, with an overwhelming suspicion that long-term sufferers will not benefit from emerging myelin repair strategies because lesions, plaques and scars cannot be fixed once formed. This post is now saying that it may not be the case.

    I seriously hope that your interpretation of myelin restoration turns out to be the correct one. I wish you luck in your investigations and hope they pay worthwhile dividends to everyone affected by MS.

    Thank you MouseDoctor.

  3. Here is the abstract of the Zivadinov study:

    "Magnetization transfer imaging of acute black holes in patients on glatiramer acetate"

    As it seems, there was no control group. As for the "significant increases" in MTR, their mean value is not mentioned in the abstract, but judging from the highest values, it might be slightly higher than the standard deviation of an MTR measurement. Great!

    After all, if copaxone was effective, we would have known by now.

  4. Dear John

    I think VV has done a fair job.

    The real question is what is MTR really detecting. Is it really remyelination.well maybe and do the MR machines have enough power to see subtle changes at the microscopic level using 1.5 tesla?.

    We could have mentioned other studies by the same group such as Zivadinov R et al. Voxel-wise magnetization transfer imaging study of effects of natalizumab and IFNβ-1a in multiple sclerosis.
    Mult Scler. 2011 Dec 22. [Epub ahead of print]. Therefore there is nothing unique to copaxone.

    If you have a drug that can inhibit the attacks you would think it should allow the natural repair mechanisms to remyelination should be expected and would not have to be drug related.

    However if it does cause repair great but how does it do it? Through the production of growth factors.

  5. Thanks MouseDoctor,

    Do you think the study at least suggested Copaxone to be effective at ‘inhibiting the attacks’?

    I’ve just stated thinking about Copaxone as a possible treatment and I’m finding it hard to find any research giving me a compelling reason to take up the habit. I thought this might be just that kind of paper, but now I’m not too sure…

  6. Maybe Prof G will answer as I don't want to advise people to take things or not. I am not qualified to do this.

    However the fact is that glaterimer acetate is an approaved MS drug and it has been shown to inhibit relapses.

    How glaterimer acetate works has changed every year since it was approved many yeas ago. If a new dogma appears I am sure it will work that way also. Researchers are lke lemmings hen it comes to dogma

    There were some reports in animal models reporting remyelination, but I think the experimental design left an area of debate about whether it was secondary to an immune effect.

    However there are are experimental studies that have been reported to show that glaterimer acetate can help save nerves (in spinal cord injury models). This would have to be a beneficial effect that cannot be attributed to an immune effect.

    Therefore talk things through with your neuro,

  7. The link to the summary does not work.

  8. Many thanks for your time - I'm due to see my neuro soon, so I'll discuss it then.

  9. Anonymous last, try

    and then the Elite Edition 2012

  10. Regarding the mouse research, Robin Franklin said 'in theory, regenerative therapies will work throughout the duration of the disease. Specifically, it means that remyelination therapies do not need to be based on stem cell transplantation since the stem cells already present in the brain and spinal cord can be made to regenerate myelin regardless of a patient's age'. But then why do you need the monocytes of a youngster, Robin, if an oldie's CNS can work just as well?

  11. Anonymous said...
    The link to the summary does not work.

    Link fixed you can at least get the figures for free if you follow the links

  12. But then why do you need the monocytes of a youngster, Robin, if an oldie's CNS can work just as well?

    Dear Anon 11:01

    If we look in MS or EAE the problem is not that there are no stem cells present to repair but that they are present but are not repairing.

    Therefore transplanting new stem cells in to MS lesions may not get over the problem of what is stopping the existing cells from not repairing. So new transplanted cells may not repair either

    Therefore I believe the Franklin approach is to find ways to get what is there to do a repair job, rather than add new repairing cells.

    In oldies there appears to be a block in repair and this new research suggests that is a problem with the engulfing cells that clear up the debris of demyelination that allows repair to occur. Youngster monocytes have not lost the X factor that allows them to trigger repair, oldies monocyte have lost their mojo that allows them to stimulate the stem cells present to cause repair. So if we can give oldies the X factor maybe they will start repairing.


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