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      Neuroprotective Effect of Transplanted Human Embryonic Stem Cell-Derived Neural Precursors in an Animal Model of Multiple Sclerosis

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          Abstract

          Background

          Multiple sclerosis (MS) is an immune mediated demyelinating disease of the central nervous system (CNS). A potential new therapeutic approach for MS is cell transplantation which may promote remyelination and suppress the inflammatory process.

          Methods

          We transplanted human embryonic stem cells (hESC)-derived early multipotent neural precursors (NPs) into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of MS. We studied the effect of the transplanted NPs on the functional and pathological manifestations of the disease.

          Results

          Transplanted hESC-derived NPs significantly reduced the clinical signs of EAE. Histological examination showed migration of the transplanted NPs to the host white matter, however, differentiation to mature oligodendrocytes and remyelination were negligible. Time course analysis of the evolution and progression of CNS inflammation and tissue injury showed an attenuation of the inflammatory process in transplanted animals, which was correlated with the reduction of both axonal damage and demyelination. Co-culture experiments showed that hESC-derived NPs inhibited the activation and proliferation of lymph node–derived T cells in response to nonspecific polyclonal stimuli.

          Conclusions

          The therapeutic effect of transplantation was not related to graft or host remyelination but was mediated by an immunosuppressive neuroprotective mechanism. The attenuation of EAE by hESC-derived NPs, demonstrated here, may serve as the first step towards further developments of hESC for cell therapy in MS.

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          Most cited references27

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          In vitro differentiation of transplantable neural precursors from human embryonic stem cells.

          The remarkable developmental potential and replicative capacity of human embryonic stem (ES) cells promise an almost unlimited supply of specific cell types for transplantation therapies. Here we describe the in vitro differentiation, enrichment, and transplantation of neural precursor cells from human ES cells. Upon aggregation to embryoid bodies, differentiating ES cells formed large numbers of neural tube-like structures in the presence of fibroblast growth factor 2 (FGF-2). Neural precursors within these formations were isolated by selective enzymatic digestion and further purified on the basis of differential adhesion. Following withdrawal of FGF-2, they differentiated into neurons, astrocytes, and oligodendrocytes. After transplantation into the neonatal mouse brain, human ES cell-derived neural precursors were incorporated into a variety of brain regions, where they differentiated into both neurons and astrocytes. No teratoma formation was observed in the transplant recipients. These results depict human ES cells as a source of transplantable neural precursors for possible nervous system repair.
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            Axonal damage in acute multiple sclerosis lesions.

            One of the histological hallmarks of early multiple sclerosis lesions is primary demyelination, with myelin destruction and relative sparing of axons. On the other hand, it is widely accepted that axonal loss occurs in, and is responsible for, the permanent disability characterizing the later chronic progressive stage of the disease. In this study, we have used an antibody against amyloid precursor protein, known to be a sensitive marker of axonal damage in a number of other contexts, in immunocytochemical experiments on paraffin embedded multiple sclerosis lesions of varying ages in order to see at which stage of the disease axonal damage, in addition to demyelination, occurs and may thus contribute to the development of disability in patients. The results show the expression of amyloid precursor protein in damaged axons within acute multiple sclerosis lesions, and in the active borders of less acute lesions. This observation may have implications for the design and timing of therapeutic intervention, one of the most important aims of which must be the reduction of permanent disability.
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              Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions.

              Recent magnetic resonance (MR) studies of multiple sclerosis lesions indicate that axonal injury is a major correlate of permanent clinical deficit. In the present study we systematically quantified acute axonal injury, defined by immunoreactivity for beta-amyloid-precursor-protein in dystrophic neurites, in the central nervous system of 22 multiple sclerosis patients and 18 rats with myelin-oligodendrocyte glycoprotein (MOG)-induced chronic autoimmune encephalomyelitis (EAE). The highest incidence of acute axonal injury was found during active demyelination, which was associated with axonal damage in periplaque and in the normal appearing white matter of actively demyelinating cases. In addition, low but significant axonal injury was also observed in inactive demyelinated plaques. In contrast, no significant axonal damage was found in remyelinated shadow plaques. The patterns of axonal pathology in chronic active EAE were qualitatively and quantitatively similar to those found in multiple sclerosis. Our studies confirm previous observations of axonal destruction in multiple sclerosis lesions during active demyelination, but also indicate that ongoing axonal damage in inactive lesions may significantly contribute to the clinical progression of the disease. The results further emphasize that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies in inflammatory demyelinating conditions.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2008
                5 September 2008
                : 3
                : 9
                : e3145
                Affiliations
                [1 ]The Hadassah Human Embryonic Stem Cells Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [2 ]Department of Neurology, The Agnes Ginges Center for Human Neurogenesis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [3 ]Department of Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [4 ]Center for Brain Research, Medical University of Vienna, Vienna, Austria
                City of Hope Medical Center and Beckman Research Institute, United States of America
                Author notes

                Conceived and designed the experiments: MA HL BR TBH. Performed the experiments: MA OE NF. Analyzed the data: MA OE BR TBH. Wrote the paper: MA BR TBH.

                Article
                07-PONE-RA-02941R1
                10.1371/journal.pone.0003145
                2522282
                18773082
                4721104f-797e-4476-8940-1e46eb86482c
                aharonowiz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 5 December 2007
                : 12 August 2008
                Page count
                Pages: 10
                Categories
                Research Article
                Developmental Biology/Stem Cells
                Immunology/Immunomodulation
                Neurological Disorders/Multiple Sclerosis and Related Disorders

                Uncategorized
                Uncategorized

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