Abstract and Introduction
The reported evidence of neurodegeneration in multiple sclerosis (MS) may explain the lack of efficacy of the currently used immunomodulating modalities and the irreversible axonal damage, which results in accumulating disability. To date, efforts for neuroprotective treatments have not been successful in clinical studies in other CNS diseases. Therefore, for MS, the use of stem cells may provide a logical solution, since these cells can migrate locally into the areas of white-matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin. This is achieved both by support of the resident CNS stem cell repertoire and by differentiation of the transplanted cells into neurons and myelin-producing cells (oligodendrocytes). Stem cells were also shown to possess immunomodulating properties, inducing systemic and local suppression of the myelin-targeting autoimmune lymphocytes. Several types of stem cells (embryonic and adult) have been described and extensively studied in animal models of CNS diseases and the various models of MS (experimental autoimmune encephalomyelitis [EAE]). In this review, we summarize the experience with the use of different types of stem cells in CNS disease models, focusing on the models of EAE and describe the advantages and disadvantages of each stem cell type for future clinical applications in MS.
Multiple sclerosis (MS) is a chronic inflammatory multifocal demyelinating disease of the CNS that affects predominantly young adults. MS is the main cause of chronic neurological disability in this age group. While its pathogenesis is still obscure, and multiple (genetic, environmental and infectious) factors seem to be involved in it, it is widely accepted that the final pathogenetic pathway is that of an autoimmune attack against myelin components. Additional mechanisms have been lately undercovered, including damage of the axons in the CNS and a degenerative process, which is probably the result of inflammation, causing accumulating and irreversible damage with time. Naturally, treatment approaches for MS focus on targeting the immune system, either in a nonspecific way (systemic immunosuppression with cytotoxic agents) or through immunomodulation (to specifically downregulate the myelin-reactive autoimmune lymphocytes or to enhance the regulatory immune networks) in order to control the inflammatory process, which, as mentioned, causes demyelination. Unfortunately, currently existing treatments for MS (both the immunosuppressive ones and the immunomodulating, i.e., glatiramer acetate and IFN-β) are only partially effective, likely owing to the limited ability of the prescribed medications to exert a significant in situ immunomodulation in the areas of lesions in the CNS, paralleled by a deficiency in growth-factor production and insufficient numbers or mobilization of the resident CNS stem cells.[2,3]
Therefore, it is obvious that, in order to improve treatment outcome in MS, innovative approaches are required for immune regulation rather than nonselective immunosuppression, as well as therapeutic interventions that may offer effective in situ immunomodulation and neuroprotection.
Extensive studies have provided strong evidence for neurodegeneration in MS, including: the finding of amyloid precursor protein accumulation in neurons; a reduction in N-acetylaspartate/creatine ratio in magnetic resonance spectroscopy, which correlates well with the degree of disability, the finding of axonal ovoids/transected axons at the edge and the core of active lesions and of oxidative damage in mitochondrial DNA and impaired activity of mitochondrial enzyme complexes; the reduction in axonal density in normal-appearing white matter (NAWM) early in MS; and a more prominent reduction of axonal density in spinal cord NAWM in progressive MS patients.[8,9]
A logical treatment approach to enhance neuroprotective mechanisms and to induce neuroregeneration in MS is with stem-cell transplantation.[2,3] Stem cells are a diverse group of multipotent cells. In general, these cells are relatively undifferentiated and unspecialized, and can give rise to the differentiated and specialized cells of the body. All stem cells exert two characteristic features: the capacity for self renewal and preserving a pool of undifferentiated stem cells; and the potential to produce various differentiated cell types. There are different kinds of stem cells that can be isolated from embryonic and adult tissues. Embryonic stem cells (ESCs) are cells derived from the inner cell mass of embryos[10,11] at the blastocyte stage (5-9 days after fertilization). The only source for human stem cells is from embryos obtained from in vitro fertilization. Adult stem cells represent a more differentiated cell population than ESCs, and can be isolated from various tissues, including muscle, adipose tissue, CNS (neural stem cells [NSCs])[14,15] and bone marrow (mesenchymal stromal cells [MSCs]).[16,17] A distinct population of non-tissue-specific multipotent adult stem cells (MAPCs) have also been isolated from the bone marrow, muscles and CNS. All of the previously described stem cells carry a potential for tissue repair. Theoretically, the use of ESCs and adult NSCs might represent the optimal source for cell-replacement therapies in CNS disorders such as MS.
In the current review, the various types of stem cells, which were mainly studied in animal models, will be reviewed as a potential therapeutic approach for MS. The main and common mechanisms of action of all stem cells include induction of neuroregeneration and remyelination through the activation of resident stem cells, or production of new CNS cell lineage progenitors, paralleled by local and systemic immunomodulating effects.
Expert Rev Neurother. 2007;7(9):1189-1201. © 2007 Future Drugs Ltd.
Cite this: Use of Stem Cells for Treatment of Multiple Sclerosis - Medscape - Sep 01, 2007.