An Interesting Article

I came across an an article on Science Daily last week that I though I would share with you guys.

As many of you know, MS is a threshold trait, therefore genome studies can only really tell a person if they are genetically susceptible to developing MS. However, a study done at the Technical University in Munich, Germany, found that an antibody (KIR4.1) may be present in a persons blood years before the symptoms of the disease arise! 

This is important because if doctors can detect the disease before the onset of symptoms they may be able to manage the symptoms better, and maybe even prevent them!!

Here is the SD article and the link to the page. Check it out if you are interested:

American Academy of Neurology (AAN). “Antibody may be detectable in blood years before MS symptoms appear.” ScienceDaily. ScienceDaily, 21 February 2014. <www.sciencedaily.com/releases/2014/02/140221184523.htm>.

 

The Fight for a Cure Continues: Could Stem Cells be Used to Reverse the Effects of Demyelination in the Central Nervous System?

Welcome back fellow bloggers!

For someone suffering from multiple sclerosis or any other debilitating disease it is always nice to have that sense of hope: the hope for a cure. Whether it is your way of staying positive or just keeping up to date on current advancements, you are always left wondering, “what if this time it works?” Currently, any research done that is hell bent on finding this cure focuses on two main concepts. The first is the prevention of damage in the central nervous system (CNS) by modulation of the immune system, which was the focus of my last blog post; and the second is finding a way to repair the damaged neurons by regenerating myelin! To date there are no treatments that effectively regenerate myelin and reverse the effects of demyelination in the CNS. Therefore, for this particular entry I am going to change up the focus a little bit and discuss new stem cell research that has been shown to promote nerve regeneration in the peripheral nervous system (PNS). When I say new, I mean VERY new… Lavasani and her team from the Pittsburgh School of Medicine publish their incredible work on March 18, 2014. Their work focused on the regenerative function of human muscle derived stem/progenitor cells (hMDSPCs) on the peripheral nervous system in mice! Now, interestingly enough, this study provides a source of potential stem cells for treatment of demyelinating diseases, and from my last blog entry we all know that multiple sclerosis falls in this category.

This team at the University of Pittsburg looked into nerve regeneration in the PNS, not the CNS, which may prompt you to wonder why I would talk about this paper on a blog that focuses specifically on MS research. Well, this is where that change in pace is coming from. This research may focus on the PNS, but as you read along I hope you pick up on some of the main points that make it a promising study in the field on MS research!

Before I dive into the details of this paper I will give you a brief background on both stem cell research and therapy, which have been hot topics for many years now. First of all, there are two broad types of stem cells: the adult stem cells and the embryonic stem cells. For this post I am going to specifically focus on the adult stem cells. Adult stem cells are isolated from bone marrow, tissue, blood, or as seen in the Lavasani et al. study, skeletal muscle. They are best described as undifferentiated cells that have the ability to differentiate and proliferate into more specialized cells. These specialized cells then have the ability to repair and even replace damaged tissues and cells, hence why they are a prime target for use in therapeutic medicine!

Like most things, however, stem cell therapy has its disadvantages. One of the major disadvantages is the fact that the immune system may recognize these cells as foreign and prevent them from performing their intended functions. In human stem cell therapy doctors get around this issue in one of two ways: immunosuppression, which is when doctors reduce the efficiency of a patient’s immune system, or the use of stem cells taken directly from the patients that need the transplant, which would dramatically reduce the chance of the cells being recognized as foreign. Now, to get around this issue in the University of Pittsburg study where they did all their work on mice, they used a severe combined immunodeficiency (SCID) transgenic mouse line. SCID mice have a deficient number of T and B-lymphocytes, and therefore a weak immune system that is unable to attack the transplanted human stem cells.

Furthermore, when stem cells derived from human skeletal muscle are grown on NeuroCult proliferation medium optimized to maintain neural stem cells in culture they are capable of differentiating into mature neuronal and glial cells, both of which are shown in figure 1. These neuronal cells are nerve cells; they are able to send information through electrical and chemical signals in both the CNS and PNS. Glial cells on the other hand, are non-neuronal cells also found in the CNS and PNS; they provide support to the neurons, maintain homeostasis, and even form myelin! Yeah that’s right, myelin… the protective layer that is damaged on the nerve cells in MS patients!

During the Lavasani et al. study they looked for the presence of certain cells within the population of hMDSPCs that successfully differentiated on the NeuroCult media. They saw a high concentration of Schwann cells, which is important because these cells are a type of myelin producing glial cell found within the PNS. Schwann cells are necessary for nerve regeneration; therefore, providing evidence that these stem cells could potentially induce full nerve restoration in living animals.

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Figure 1: The structure of a glial cell (on the left) and a nerve cell (on the right).

Lavasani et al. gave these hMDSPCs cells a chance to restore cell and tissue damage by transplanting them into SCID mice with an experimentally induced sciatic nerve injury. The sciatic nerve is responsible for proper limb movement; therefore, mice with the injury are unable to walk because their nerve is cut! Only 6 weeks after transplantation with hMDSPCs the mice had complete nerve regeneration, both visually and functionally! What I mean by this is that the nerve was healed in the area that was cut, and the mice were capable of walking normally plus they gained back full strength of their injured leg. Next, researchers took a cross section of this regenerated nerve and stained for neurofilaments, found along the axon of nerve cells, and myelin, the protective coat surrounding the axon (refer to figure 1). These cross sections told an interesting story because the presence of neurofilaments surrounded by myelin was seen in the hMDSPC treated mice and the non-injured controls, however, was not seen in the injured mice that did not undergo treatment. Also, the concentration of those myelin producing glial cells, the Schwann cells, was high in the regenerated nerves, which is exactly what you would hope to see because these cells would be reproducing the myelin damaged at the site of injury, as well as facilitating axonal growth; therefore, allowing the passage of normal electrical signals and eventual nerve regeneration.

So, transplantation with human muscle-derived stem/progenitor cells allows for nerve regeneration, but how?

It is important to note here that MDSPCs have been used in previous studies that have found that the donor cells were not present in all areas that you could visualize their regenerative function. In Lavasani’s study they saw similar results: at the site of injury the host cells were present in much greater concentrations then the donor cells. This suggests that these stem cells promote changes in the host cell activity leading to nerve regeneration that is independent of neurogenesis, which is the process of generating neurons by neural stem and progenitor cells. This observed nerve healing in the Lavasani study was credited to paracrine signaling between the donor cells and the host cells. First, fibroblast growth factors (FGF) are secreted by the stem cells. FGFs are paracrine factors that diffuse over relatively short distances and simulate the growth and differentiation of nearby cells. The secretion of FGF then leads to the differentiation and proliferation of surrounding host cells toward a supporting cell lineage, and in the University of Pittsburg study that lineage was the Schwann cells. Figure 2 shows a simplistic model of the paracrine-signaling pathway involved in host cell differentiation and proliferation at the site of nerve damage.

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Figure 2: Paracrine signaling pathway resulting in nerve regeneration in the PNS. (A) The hMDSPCs secrete fibroblast growth factors (pink). The FGF then interact with the host cells (purple) located at the site of injury. (B) Host cells differentiate into Schwann cells (red). (C) Schwann cells proliferate. (D) Regeneration of the myelin surrounding the axon of nerve cells.

The Lavasani et al. study is causing some serious waves in the MS community. The approach used in this paper was on an acute nerve injury, however, shows potential for the rehabilitation in chronic diseases as well! It would be interesting to see the effects that hMDSPCs have on mice with an induced form of MS (EAE). The hope is that if these stems cells are capable of differentiating into Schwann cells when transplanted into the PNS, they will be capable of differentiating into oligodendrocytes when transplanted into the CNS. Oligodendrocytes are also glial cells responsible for the regeneration of myelin, but this time in the central nervous system. Therefore, oligodendrocytes would be directly involved in the nerve repair that is needed in order to reverse the damaged seen within the CNS of MS patients and EAE mice. If hMDSPC transplantation results in nerve regeneration within the CNS of these EAE mice, a potential treatment for MS in humans could be the injection of these stems cells into their central nervous system through the cerebrospinal fluid!

The advancements made in this study have massive potential for the future of all demyelinating diseases, including MS. Research looking into the effects that hMDSPCs have on various demyelinating diseases is ongoing, but hopefully this paper will lead to some pretty amazing treatments for the future. Could hMDSPC transplants be the first treatment established that could effectively reverse the damage caused in the CNS of MS patients? Clearly, more research is needed in order to answer this question, BUT Lavasani and her team have provided enough evidence to get that ball rolling!

The Sunshine Vitamin: Could Bathing in the Sun be a Potential Treatment for Patients with Multiple Sclerosis?

su hondy sun

Growing up it was difficult for me to think of the positive attributions the sun could have towards my health when society was constantly reminding me of all the bad things that could potentially result from the hours upon hours I spent running around or swimming outdoors in the summer. “Put on sunscreen,” “wear a hat,” and “you should be wearing long sleeves” were a few of the common remarks I would hear from various elementary school teachers and, of course, my mother. Now, over exposure to the sun is known to speed up the affects of aging as well as increase a person’s risk of developing skin cancer; however, not getting enough exposure to the sun has historically been shown to cause serious heath problems as well. Basically, what I am trying to say is that sun exposure is a two-way street when it comes to a person’s health, and a growing body of evidence shows that high exposure to the sun may have very positive effects on a person suffering from Multiple Sclerosis (MS).

IMG_1881The effects that the bioactive form of the vitamin D you get from the sun, 1,25(OH)2D3 (molecule shown to the left), has on people suffering from MS has been a field of study for many years, and it all began with the observation of a strange geographic distribution with respect to the incidence of MS: the number of people diagnosed along the equator was about 1-2 people for every 100 000, whereas the number of people diagnosed in the northern hemisphere was over 200 people for every 100 000. This trend is very important because it shows that the incidence rate of MS is much lower in countries exposed to ample amounts of sunlight year round, and in the countries, like Canada, where sunlight is less available the incidence rate increases tremendously! So, take note, because I will refer back to this distribution multiple times through out my post.

Piles of epidemiological studies have been completed that just keep restating this distribution, but minimal work has been done to see what is actually happening at a molecular level. Grishkan et al, from the Johns Hopkins University of Medicine published his work this past December, which focused on the effects of 1,25(OH)2D3 on mice with an induced form of MS – experimental autoimmune encephalomyelitis (EAE).

In both humans with MS and the related mouse model, the root problem is the same: myelin specific T cells, which are T cells targeted to the central nervous system, are primed in the lymph nodes by their particular antigen and then differentiate into effector T cells. These effector T cells travel into the blood stream until they are eventually captured by alpha integrins located on the blood brain barrier wall (BBB), and with the help of chemokines and matrix metalloproteinases, the reactive T cells enter the CNS and attack the protective layer (myelin sheath) surrounding the nerve cells, resulting in demyelination. This damage consequently leads to the loss of the electrical signals that control movement, speech, and vision. This pathway is an important target for many drugs because if you could prevent the migration of these reactive T cells into the CNS, you could potentially prevent the symptoms of both MS and EAE.

In 1991, two men by the names of Lemire and Archer treated mice with vitamin D3, then induced EAE and found that the symptoms of the disease were completely prevented; however, they had no idea what was going on at a more biochemical level. Two important predictions were made over the last 23 years that were based off of this study done by Lemire and Archer as well as the many epidemiological studies:

  1. A lack of vitamin D was triggering the disease in genetically susceptible people and,
  2. The vitamin D was inhibiting the initial activation of these reactive T cells.

Both of these predictions would consequently result in the prevention of MS and EAE symptoms, BUT they are just predictions. Therefore, Grishkan and his team at Johns Hopkins focused on the trafficking of these myelin reactive T cells to the CNS, trying to determine what role vitamin D3 plays in EAE prevention.

In the Johns Hopkins study, mice treated with vitamin D3 for 8 consecutive days before induction of EAE were monitored to see the levels of primed T-cells in their blood stream, brain, and spinal cord – what they found was very telling. The concentration of myelin specific reactive T cells in the bloodstream was very high; however, the concentration of these T cells in the brain and spinal cord was almost zero. This suggests that the vitamin D3 is preventing T cells, which are primed to attack the nerve cells in the CNS, from infiltrating into the area where they will cause real damage. These results contradict what past researchers had predicted: vitamin D deficiency is not triggering the disease in genetically susceptible people, and it is not preventing the activation of these disease causing T cells. Instead, the data provide strong and unique evidence that the bioactive form of vitamin D3 prevents EAE by modifying the pathogenic T-cells in a way that blocks them from migrating across the BBB and infiltrating into the CNS.

Keep in mind that the work completed at Johns Hopkins was done on mice with EAE, so before jumping to conclusions it is important that they figure out whether or not vitamin D3 works the same way in humans with MS. The epidemiological studies showing that strong distribution support the data found in this particular study because the incidence rate is so low along the equator. Also, way back in 1986, when the theory that vitamin D3 plays an important role in MS was new, a man by the name of P. Goldberg looked into the effects that vitamin D supplements had on MS patients. His study showed a decrease in the severity of the symptoms after patients were taking these supplements for 2 years. Although Goldberg did not look into the concentration of myelin specific T cells in the CNS of these patients, his results support those found by Grishkan because they also show a decrease in symptoms, but this time in a human model of MS.

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Basically, if the results found from the Johns Hopkins study can be better connected to the human form of MS, they would suggest that people who are genetically susceptible to Multiple Sclerosis, and whose myelin specific T cells have been activated by some environmental factor, will not show symptoms because the cells will not be able to cross the BBB to cause damage in the CNS. Grishkan and his team predict that vitamin D3 inhibits these myelin specific T cells by regulating molecules involved in their trafficking to the CNS, perhaps by promoting the secretion of a ‘sticky substance’ causing the cells to cling to the blood vessel walls, preventing their capture and subsequent migration into the CNS. The image above shows a cartoon depiction of this hypothesis!

During the Johns Hopkins study, mice exposed to vitamin D for long periods of time did not show symptoms of EAE, but only 4 days after the treatment with vitamin D was removed the mice began to show symptoms! The fact that their symptoms appeared so quickly after treatments were removed further suggests that the T cells are already primed and ready to attack, only the vitamin D3 is holding them back. This reversibility raises some interesting questions. First of all, could someone who has lived along the equator their whole life have these disease causing T cells present within their bloodstream without them knowing about it until they move to a place like Canada or the US? Also, could the data found in the Johns Hopkins study finally be an answer to this strange geographic distribution?

To further these findings and answer these questions, an epidemiological study could be done to see whether patients living with MS further north of the equator show less severe symptoms in the summer months compared to the winter months, when sunlight is less available. Also, Grishkan et al. findings give researchers an opportunity to study blood samples taken from MS patients and controls to see if vitamin D3 is having the same effect on human cells, as it appears to be having on the mice cells. Compiling the data from all these studies could potentially lead to new and safer treatment plans!

Image if all you needed to relieve your painful symptoms of MS was a nice long vacation in the sun, getting all the sunshine vitamin your body needs!