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.
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.
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!