By: Jeremy Yam Ting Ho

Multiple Sclerosis (MS) is an autoimmune disease and a neurodegenerative disease in the Central Nervous System. Its symptoms are indicated as loss of oligodendrocytes, demyelination and degeneration of neurons and inflammation [1]. The recurring inflammation and damaged oligodendrocytes prolongs and worsens the regeneration of neurons, which leads to chronic MS lesions followed by neurological dysfunction [8]. Current therapies focus on using both the anti-inflammatory drugs and immunomodulatory drugs, but if the damage is too austere the drug will be ineffective [1]. Data shows only 30% of the population benefit from current therapeutic drugs [1]. It is important for alternative therapies that allow for long term recovery on MS patients. These therapies need to focus on remyelination and regeneration of CNS neurons and downregulation of chronic inflammation. Such therapies may include the use of stem cells or drugs that can modulate immune response.

1. Stem cell therapy –Mesenchymal stem cells

Mesenchymal cells (MSC) are multipotent progenitor cells; they are self-renewing and capable of multi lineage differentiation such as myocytes, neurons and so on [1]. MSC can be found in the bone marrow, liver, adipose tissue and so on. Current pilot clinical studies show MSC’s safety and feasibility for MS; there is also a new protocol to generate single cell-derived clonal Mesenchymal stem cell lines [5]. An issue with MSC is the chance of immune-rejection from the donor’s immune system upon receiving donor cells [4].

1.a Immunomodulatory cells

MSC alone can act as an immunomodulatory cell; it can regulate several immune cells such as T cell, B cell, Natural killer cells and dendritic cells (figure 1.) [1]. There is a lack in T cell response and altered cytokine production as allogeneic MSC are transplanted into tissues in vitro [4]. MSC suppresses the T cell proliferation by secreting TGFβ (transforming growth factor beta) and HGF (hepatocyte growth factor) and decreasing cytokines like TNFα (Tumor necrosis factor alpha) [4]. Further evidence has demonstrated MSC has long term engraftment in the utero of lambs that lasted up to 13 months. This is also evident in skin graft studies with baboons [4].

Figure 1. The immunoregulatory properties of mesenchymal stem cells (Song and Yi, 2012)

1.b Neuromodulatory cells

MSC shows a relatively low likelihood to migrate and integrate into the Central Nervous System [1]. Instead, MSC functions through promotion of endogenous repair processes such as recruiting Oligodendrocyte precursor cells (OPC) to differentiate [1], [5]. MSC also showed secretion of soluble chemoattractants that draws in Neural Progenitor cells (NPC) [1]. NPC is responsible for the regeneration of neuronal cells [1] and OPC is important in the remyelination repair of axons [7]. Both OPC and NPC reside at the subventricular zone and the subgranular zone of the dentate gyrus [1]. However, MSC can be induced and differentiate into neurons or glial cells via the addition of growth factors or small molecules. Evidently, MSC still remains a method to recruit endogenous repair, in addition to the recruitment of neurotropic factors like BDNF and NT3 via OPC and NPC [7]. Neutrophic factors functions for neuroprotection and promotes regeneration, in particular for NT3 and BNDF; which enhances Oligodendrocyte proliferation and survival [7].

2. Disinhibition of inhibitory molecules in CNS

One of the major issues with MS is the ongoing inflammatory response, which inhibits the process of neuronal recovery. With chronic demyelination, certain proteins arise from the damaged neuron remnants [2]. Some of these proteins include Semaphorin 3A which is important in OPC regulation [2] and immune cells such as chemokines and cytokines that are upregulated during neurodegeneration and neuroinflammatory response [6]. Both proteins are involved with astrocyte and microglia response in the body [6].
Figure 2. Diagram showing possible members of the Semaphorin protein family (Kumanogoh et al., 2011)
Figure 2. Diagram showing possible members of the Semaphorin protein family (Kumanogoh et al., 2011)

2.a Down-regulation of Semaphorin 3A

Semaphorin is a large family of proteins that are involved in cell migration control and axonal growth cues (Figure 2.) Some of these proteins can promote chemo cell to cell communication, either repulsive or attractive [10]. An example of this would be Semaphorin 3A; it is a secretory protein of the Semaphorin family [10]. Semaphorin 3A can be secreted by macrophages and OPC. It binds on to the Sema receptor NP-1; exerts it negative cue effects on OPC migration and differentiation. Semaphorin 3A is also involved in peripheral axon growth and regulating the trajectory of neurons [6]. In MS lesions, this receptor is highly expressed in the OPC especially at low inflammation stages [2]. Therefore, Semaphorin 3A acts as a regulator that inhibits OPC differentiation in the feedback loop. Evidence establishes that Semaphorin inhibits CNS myelination in vivo [2]. A possible solution involves drugs that target the Semaphorin 3A signaling, such as RhoA; a signaling effector for Semaphorin 3A [10]. By down-regulation on the feedback loop, more OPC can differentiate and promote remyelination. Semaphorin 4D is a future protein candidate for therapeutic targeting [9]. It effects are similar to Semaphorin 3A; but it promotes apoptotic behavior, activation of immune cells such as B cells, dendritic cells and so on (Figure 3.). Evidence shows the KO of Semaphorin 4D, indicates an upregulated expression of OPC [9].

Figure 3. Showing a diagram for a possible model for inflammation response in Multiple Sclerosis (Kumanogoh et al., 2011)
Figure 3. Showing a diagram for a possible model for inflammation response in Multiple Sclerosis (Kumanogoh et al., 2011)

2.b Inhibition of Chemokine signalling

Chemokines are small proteins that promote leukocyte (white blood cell) migration to inflammatory response sites [6]. As a family of Chemokines, they are separated into 4 groups: C, CC, CxC and Cx3C. Chemokines bind onto a G coupled protein Chemokine receptor and employ their effects through a downstream signaling pathway. The chemokine receptors are separated into three groups; (i) restriction of inflammatory response, (ii) recruitment and migration of regulatory cells and (iii) trafficking of immune cells [3]. Examples of these chemokine receptors are CxCR3/4 for group 1, CCR4/7 for group 2 and CCR1/2/5 for group 3. However, chemokines are also involved in other processes such as angiogenesis, CNS formation and so on [3]. It is therefore important to consider the overall effect of the drug that is antagonist to the chemokine receptor. Currently the only drugs that are in clinical trial phase II are antagonist to the CCR1 and CCR2 receptor such as BX471 and CCx915/MK-0812 respectively [3]. Both CCR1/2 are important in recruiting immune cells such as T cells where inflammation follows. Hence, by inhibiting both receptors less inflammation would occur.

3. Achieving remyelination and regeneration in CNS neurons

The body naturally regenerates and remyelinate damaged neurons in the CNS, but inhibitory proteins/molecules and inflammation persists to tamper this process especially in MS patients. Alternative therapies are generated to tackle this problem and provide a long term beneficial effect for MS patients. These therapies include use of Mesenchymal stem cells and targeting inhibitory molecules/proteins in the central nervous system. Both methods have been initiated through in vivo studies and clinical trials. MSC has demonstrated its ability as an immunomodulatory cell by suppression of T cell expression. MSC can also act as neuromodulator indirectly by recruitment of endogenous repair via OPC and NPC. The suppression of inflammatory response includes drugs that inhibit immune cell recruitment by chemokine receptor antagonist. This also includes the hindrance of Semaphorin 3A; an OPC differentiation regulator.

4. Reference

[1] Bernard, C.A., Payne, N., Siatskas, C., (2008) The promise of stem cell and regernative therapies for multiple sclerosis. Journal of Autoimmunity 31,288-294
[2] Hand, E., Hofer, M., Kotter, M.R., Mӧbius, W., Nave, K.A., Syed, Y.A., Zhao, C. (2011) Inhibition of CNS remyelination by the presence of Semaphorin 3A. The Journal of Neuroscience 31:10,3719-3728
[3] Hamman, I., Infante-Duarte, C., Zipp, F. (2008) Therapeutic targeting of chemokine signaling in Multiple Sclerosis. Journal of the Neurological Sciences 274, 31-38
[4] Beggs,K.J., Deans, R.J., Klyushnenkova, E., Majumdar, M.K., McIntosh, K.R., Mosca, J.D., Simonetti, D.W., Zernetkina, V. (2005) T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. Journal Of Biomedical Science 12,47-57
[5] Song, S.U., Yi, T., (2012) Immunomodulatory properties of Mesenchymal stem cells and their therapeutic applications. Archives of ParmacalResearch 35:2, 213-221
[6] Belmadani, A., Miller, R.J., Ren, D., Tran, P.B. (2006) Chemokines Regulate the migration of neural progenitors to sites of neuroinflammation. The Journal of Neuroscience 26:12, 3182-3191
[7] Gage, F.H., Horner, P.J., McTigue, D.M., Stokes, B.T. (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. The Journal of Neuroscience 18:14, 5354-5365
[8] Wolswijk, G. (1998) Chronic Stage Multiple Sclerosis Lesions contain a relatively quiescent population of Oligodendrocyte precursor cells. The Journal of Neuroscience 18:2, 601-609
[9] Furuyama, T., Inagaki, S., Kageura, M., Tamai, R., Yamaguchi, W. (2012) Sema4D as an inhibitory regulator in Oligodendrocyte development. Molecular and Cellular Neuroscience 49, 290-299
[10] Aunis, D., Bagnard, D., Crémel, G., Koncina, E., Roth, L., Satkauskas, S. (2009) The many faces of Semaphorins: from development to pathology. Cellular and Molecular Life Sciences 66, 649-666
[11] Kumanogoh, A., Nakatsuji, Y., Okuno, T. (2011) The role of immune Semaphorins in Multiple Sclerosis. Federation of European Biochemical Societies Letters 585:23, 3829-3835.

5. See also

Multiple Sclerosis

Theories of Origin and Risk Factors

Pathophysiology of Multiple Sclerosis

Clincal Symptoms and Diagnosis

Multiple Sclerosis Modifying Treatment