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

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