Sunday, 19 June 2016

Mesenchymal Stem Cells fail to hit the mark. An isolated study or the voice of reason?


Abramowski P, Krasemann S, Ernst T, Lange C, Ittrich H, Schweizer M, Zander A, Martin R, Fehse B. Mesenchymal Stromal/Stem Cells Do Not Ameliorate Experimental Autoimmune Encephalomyelitis and Are Not Detectable in the Central Nervous System of Transplanted Mice. Stem Cells Dev. 2016. [Epub ahead of print]
Mesenchymal stromal/stem cells (MSCs) constitute progenitor cells that can be isolated from different tissues. Based on their immunomodulatory and neuroprotective functions, MSC-based cell-therapy approaches have been suggested to antagonize inflammatory activity and neuronal damage associated with autoimmune disease of the central nervous system (CNS), e.g. multiple sclerosis (MS). Intravenous MSC transplantation was reported to ameliorate experimental autoimmune encephalomyelitis (EAE), the mouse model of MS, within days after transplantation. However, systemic distribution patterns and fate of MSCs after administration, especially their potential to migrate into inflammatory lesions within the CNS, remain to be elucidated. This question has of recent become particularly important, since therapeutic infusion of MSCs is now being tested in clinical trials with MS-affected patients. Here we made use of the established EAE mouse model to investigate migration and therapeutic efficacy of mouse bone-marrow derived MSCs. Applying a variety of techniques, including magnetic-resonance imaging, immunohistochemistry, fluorescence in-situ hybridization, and quantitative PCR we found no evidence for immediate migration of infused MSC into the CNS of treated mice. Moreover, in contrast to other studies, transplanted MSCs did not ameliorate EAE. In conclusion, our data does not provide substantiation for a relevant migration of infused MSCs into the CNS of EAE mice supporting the hypothesis that potential therapeutic efficacy could be based on systemic effects. Evaluation of possible mechanisms underlying the observed discrepancies in MSC-treatment outcomes between different EAE models demands further studies.

With alot of fanfare stem cells have been touted as the next great hope. The public has demanded that there is stem cell work and trials and all that stuff.

A number of studies have been published and claiming that there is an inhibitory effect on the immune response, the transplanted stem cells injected get to the blood are reported to get into the brain by the same mechanism that white cells get into the brain and then they turn into oligodendrocytes and nerves. 

The problem is when you take a step back and look at the animal data the inhibitory effect on the immune response is often marginal and much worse than that that could easily be obtained with fingolimod. Most of the cells injected are gone within a week and don't differentiate into nerves and oligodendrocytes (It's claimed their cytokines make stem cells present in the lesions re-awaken). 

In my mind not the best data to launch a trial.

This paper argues it is hogwash and that mesenchymal stem cells don't even induce an immune-inhibitory effect, don't get in the brain and don't magically turn into nerves to turn back time.

This paper has spent alot of resource, desparately trying to see a positive effect and finding nothing.  This is a small ship riding against a tide of optimsm. 

How many more studies are out there support this view? We repeatedly saw failure of stem cells as immunomodulatory agents. What trick did they(we) miss to get a positive result?

Does this provide a prelude for what we will see actually in the human studies, because they are unlikely to have the prefect conditions for everyone.

What ever the result you can't now say that animal studies got it wrong:-).

However, does clinical acute EAE in mice really show demyelination/ remyelination. I am yet to be convinced that the way it is used is the most appropriate to show remyelination?  But I'm a lone voice banging my head against a brick wall. 

In so many repair studies we see the treatments inhibiting the clinical disease before the damage is really done. I would expect that a true remyelination agent would not stop the damage from developing but may promote a more rapid recovery. When I see a big effect at inhibiting EAE, I am more likely to think immunosuppression or fluke, rather than wow remyelination. However, a big effect on clinical EAE has become the result that people want to see and demand is shown.  

Plaisted WC, Zavala A, Hingco E, Tran H, Coleman R, Lane TE, Loring JF, Walsh CM.Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis. PLoS One. 2016;11(6):e0157620.
Clinical trials have been initiated and should be reported soon. I guess you can see what I think maybe the outcome...be warned

15 comments:

  1. Mouse,

    The stem cell efforts have moved on with humans now being tested e.g.. dr Freedman's trial. This sorts of human trials should provide real answers and identify how such therapies could be improved. Why are mouse models still being used?

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    1. I don't think people are doing much with hsct in animals.

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    2. Sorry you are wrong the freedman stuff is something that was being done in mice in the 80s. This is about immune replacement it has nothing to do about repair and neuros rotation.

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    3. Anecdotally, the Freedman trial stated that 6 participants felt they had enough gains to return to work. There is no granular reporting of what symptoms went away or for that matter. Before, during and after MRI's would be telling in respect to remyelination.

      One would presume *IF* significant myelination happened those MRI's would be floating around the web as much as the headlines have.

      To me, the fact 1 in 24 died as a direct result is significant. Two others died within 3 years and was stated to not be in any relation to the therapy. Ok, then how?

      If it were car accidents then its car accidents.

      If its due to a medical reason then that all becomes "oh really?"

      Its not like the pathology of stem cell treatments are refined. If person "A" had a cardiac arrest and died... No that does not seem be related. On the other side of the coin patients billions of cells, synaptic function were not monitored at each moment. They cant be. Thus if they died due to a medical condition saying "It was not related to the therapy" is as anecdotal as saying it was. Or, as anecdotal as saying this case of PML was caused due to Tecfidera. The PML was caused by the JC Virus. The patient may well (perhaps not likely) had PML infection on Gilenya, Tysabri or even taking immunosuppressive supplements... even nothing at all.

      If a trial in the USA for aspirin had 1 in 24 die, three within three years there would be no phase III as the FDA would step in.

      Thats not to say that one person who died would be shown in a phase III larger cohort, aka 4 in 100.

      I think Dr. Freedmans work is remarkable but they need proceed very very cautiously forward. *IF* a phase III trial with whatall, 500 people had 5 die as a result, 10 others within 5 years claimed as to be unrelated but due to a medical circumstance it could well set back MS stem cell research a long long ways as care systems go, "Ummm... No, this is not what we want to do."

      Stem cell researchers across many other disciplines (and I know several) are quite concerned about what one rather well known researcher deemed "pocket research". Very bad events could set back stem cell research in enormous fashion across a variety of conditions, not simply MS. I was told that for the most part Stem Cells are very likely to provide many miracles for many people. But stem cell treatment towards chronic level conditions is not ready yet. Not enough is known essentially.

      That party akin'd research on humans to be a "Lets try this and see what happens" based on very little scientific knowledge of stem cells which is highly complex science.

      It was cited to me as, "Would we just send people into space in an relatively unknown spacecraft. Then when the results of that journey resulted in the people aboard the craft dying or not being able to come back, what happens to that open access to space flight? It ends."

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  2. The goal of a-HSCT is to reconstitute the immune system that has gone awry and restore tolerance to the putative autoimmune lymphocytes that drive MS. The conditioning step would ablate the immune system, including the lymphocytes in the CNS that are supposedly driving inflammation in RRMS. Why would MSCs be thought to be anti-inflammatory and ameliorate EAE? If the effect of HSCT on EAE is to be studied the mice should have their immune systems reset after induction of EAE and reconstituted with progenitor cells as done by Dr. Freedman and Dr. Burt. Would EAE in mice be stopped by such a procedures?

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    1. You are correct it is an immune reset. The freedman and burt stuff is just an extension of bone marrow transplants started in the 70s-80s in eae

      The stem cells that many people crave are neurosescorting ones mcsc have been claimed to be this.

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  3. MD I'm willing to place a bet with these mesenchymal stem cell guys, if one of them can show me convincing data that it is reproducible, I'll hand wash their car for an year!

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    1. Okay they'll probably win the Nobel prize or something!

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  4. This result is not surprising at all. What is surprising is that researchers try to give HSCT via IV access into the peripheral vascular system? These cells are supposed to somehow maneuver the peripheral vasculature and cross the BBB into areas of inflammation with all sorts of antagonistic immune forces at work in the brain/spinal cord of MS/EAE and expect it to work?

    A researcher with imagination would not use IV access. They would at least try to dampen inflammation prior to administration of HSCT. They would use a vehicle/microsome/liposome to try to safely transport the HSCT across the BBB, much like current oncologist researchers are trying with chemotherapy for difficult to access/treat brain tumours currently. These are early days of HSCT and one day some innovative researcher will figure how to safely get HSCT across the BBB to where they are supposed to be in a supportive environment.

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    1. HSCT is about replacing the immune system, don't kid yourself that it is something about repair, it isn't, unless the immune system can produce a growth factor, which has to get into the CNS.

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    2. Sorry I meant MSCs not HSCTs and totally agree with you.

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    3. The issue is making the cells to migrate into the right place and not somewhere else and then to differentiate into a cell type hat you want and not something that you don't , all the while hoping that someone has not already messed up and failed and killed off the interest in the approach.

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    4. All that said... Recently an experiment happened with chronic stroke patients whereby stem cells (not even theirs as I understand it) were placed directly over damaged areas in their brains.

      Holes were drilled in their skulls basically and stem cells dumped in.

      The results were that the stroke patients had significant gains. Very significant gains in fact. I'll see if I can find the article.

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    5. Quite fascinating.

      https://med.stanford.edu/news/all-news/2016/06/stem-cells-shown-safe-beneficial-for-chronic-stroke-patients.html

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