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

Abstract

BackgroundMultiple 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.MethodsWe 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.ResultsTransplanted 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.ConclusionsThe 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.

Cell Therapy for Multiple Sclerosis

“…NPC transplantation in MOG35-55-induced EAE mice attenuated brain inflammation, reduced acute and chronic axonal injury and demyelination, and improved the overall clinical and neurophysiological performance of the CNS of the mice [173,174]. Finally, such immune regulatory properties were also shown for human embryonic-stem cellderived NPCs in rodents [151] and for somatic NPCs in primates [175]. Again, the therapeutic effects of both these latter NPC sources was not related to graft-or host-driven remyelination, but rather were mediated by an immune regulatory mechanism that protected the CNS from immunemediated injury [151].…”

“…Finally, such immune regulatory properties were also shown for human embryonic-stem cellderived NPCs in rodents [151] and for somatic NPCs in primates [175]. Again, the therapeutic effects of both these latter NPC sources was not related to graft-or host-driven remyelination, but rather were mediated by an immune regulatory mechanism that protected the CNS from immunemediated injury [151].…”

“…However, EAE has not proven useful for developing the cell transplantation approach for remyelination. A central problem is that the existing chronic EAE models have an extensive axonal pathology at the early acute phase, which does not allow any myelin repair [151]. Thus, there is urgent need for a clinical relevant model of remyelination failure where the potential of cell therapy may be examined properly.…”

Stem Cell Therapy for Amyotrophic Lateral Sclerosis

“…The integration ability and prospective therapeutic efficacy of human neural stem cells (hNSC) has been demonstrated in rodent models of neurological diseases [20][21][22][23]. Apart from regenerating lost neuronal cells, NSCs can also improve the functional outcomes of rats through auxiliary mechanisms, such as neurotrophism [24][25][26] and immunosuppression [27][28][29].…”

Neural Differentiation of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells

“…Embryonic stem cells (ESCs), neural stem cells (NSCs), bone marrow (BM)-derived mesenchymal stem cells (MSCs), and adipose-derived adult stem (ADAS) cells have been shown to generate differentiated neural cells both in vitro and in vivo, which can be used as substitute therapies for various neurodegenerative diseases (1)(2)(3)(4)(5). However, despite the differentiation capability of these cells, ethical conflicts, legal restrictions, the invasive procedures required to obtain them, and graftversus-host disease (GVHD) are major challenges in their development for clinical applications that emphasize exploring and evaluating different sources for use in various cell-based therapies (1,6). MSCs have been shown to be ideal candidates for regenerative medicine (7).…”