Abstract
BackgroundMultiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. There is no cure for MS. We used a novel approach to investigate the therapeutic potential of neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS.MethodsMSCs were differentiated into NSCs, labeled with PKH26, and injected into the tail vein of EAE mice. Neurobehavioral changes in the mice assessed the effect of transplanted cells on the disease process. The animals were sacrificed two weeks following cell transplantation to collect blood, lymphatic, and CNS tissues for analysis. Transplanted cells were tracked in various tissues by flow cytometry. Immune infiltrates were determined and characterized by H&E and immunohistochemical staining, respectively. Levels of immune regulatory cells, Treg and Th17, were analyzed by flow cytometry. Myelination was determined by Luxol fast blue staining and immunostaining. In vivo fate of transplanted cells and expression of inflammation, astrogliosis, myelination, neural, neuroprotection, and neurogenesis markers were investigated by using immunohistochemical and qRT-PCR analysis.ResultsMSC-derived NSCs expressed specific neural markers, NESTIN, TUJ1, VIMENTIN, and PAX6. NSCs improved EAE symptoms more than MSCs when transplanted in EAE mice. Post-transplantation analyses also showed homing of MSCs and NSCs into the CNS with concomitant induction of an anti-inflammatory response, resulting in reducing immune infiltrates. NSCs also modulated Treg and Th17 cell levels in EAE mice comparable to healthy controls. Luxol fast blue staining showed significant improvement in myelination in treated mice. Further analysis showed that NSCs upregulated genes involved in myelination and neuroprotection but downregulated inflammatory and astrogliosis genes more significantly than MSCs. Importantly, NSCs differentiated into neural derivatives and promoted neurogenesis, possibly by modulating BDNF and FGF signaling pathways.ConclusionsNSC transplantation reversed the disease process by inducing an anti-inflammatory response and promoting myelination, neuroprotection, and neurogenesis in EAE disease animals. These promising results provide a basis for clinical studies to treat MS using NSCs derived from primitive MSCs.
Highlights
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS)
Our results demonstrated that EAE disease symptoms were reduced or reversed and significant improvements were observed in the pathology of the CNS in animals transplanted with mesenchymal stem cells (MSCs) and neural stem cells (NSCs), with the latter being the more effective
Differentiation of primitive MSCs into NSCs and oligodendrocytes cells (ODCs) Primitive MSCs were induced towards the neural lineage by culturing the cells in induction media containing 10 μg epidermal growth factor (EGF; PeproTech, Rocky Hill, NJ, USA) in DMEM/F12 basal medium supplemented with 5.6% antibiotic solution for 3 days
Summary
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Several reports describe the ability of neural stem cells (NSCs) to migrate to the area of pathology in experimental models of CNS diseases [10, 11]. We applied a novel cell therapy approach whereby highly proliferative and naïve primitive MSCs were first differentiated into NSCs that were transplanted into an experimental autoimmune encephalitis (EAE) mouse model, which is known to share similar characteristics and pathological features with MS [15]. Our results demonstrated that EAE disease symptoms were reduced or reversed and significant improvements were observed in the pathology of the CNS in animals transplanted with MSCs and NSCs, with the latter being the more effective. These studies demonstrate that NSCs derived from primitive MSCs have therapeutic potential to treat MS and other neurodegenerative diseases
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