ABSTRACT
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ABSTRACT
Oligodendrocyte precursor cells (OPCs) have the ability to repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. Recent evidence suggests that miR-219 helps regulate the differentiation of OPCs into oligodendrocytes. We performed oligodendrocyte differentiation studies using miR-219-overexpressing mouse embryonic stem cells (miR219-mESCs). The self-renewal and multiple differentiation properties of miR219-mESCs were analyzed by the expression of the stage-specific cell markers Nanog, Oct4, nestin, musashi1, GFAP, Tuj1 and O4. MiR-219 accelerated the differentiation of mESC-derived neural precursor cells (NPCs) into OPCs. We further transplanted OPCs derived from miR219-mESCs (miR219-OPCs) into cuprizone-induced chronically demyelinated mice to observe remyelination, which resulted in well-contained oligodendrocyte grafts that migrated along the corpus callosum and matured to express myelin basic protein (MBP). Ultrastructural studies further confirmed the presence of new myelin sheaths. Improved cognitive function in these mice was confirmed by behavioral tests. Importantly, the transplanted miR219-OPCs induced the proliferation of endogenous NPCs. In conclusion, these data demonstrate that miR-219 rapidly transforms mESCs into oligodendrocyte lineage cells and that the transplantation of miR219-OPCs not only promotes remyelination and improves cognitive function but also enhances the proliferation of host endogenous NPCs following chronic demyelination. These results support the potential of a therapeutic role for miR-219 in demyelinating diseases.
Subject(s)
Demyelinating Diseases/genetics , Demyelinating Diseases/physiopathology , MicroRNAs/metabolism , Oligodendrocyte Precursor Cells/transplantation , Recovery of Function , Remyelination/genetics , Animals , Axons/metabolism , Cell Differentiation , Cell Lineage , Cell Proliferation , Cell Survival , Chronic Disease , Coculture Techniques , Cognition Disorders/physiopathology , Cognition Disorders/therapy , Cuprizone , Disease Models, Animal , Mice , MicroRNAs/genetics , Pluripotent Stem Cells/metabolismABSTRACT
Studies have indicated that glutamate receptor subunit 3 peptide B antibodies (GluR3B Ab's) by directing against a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype glutamate receptors (AMPARs) subunit 3 (GluR3B) was involved in the hippocampal neuron damage in the pathogenesis of epilepsy. Glutamate accumulation is critical for oligodendrocyte precursors (OPCs) excitotoxic injury. However, remarkably little is known about whether GluR3B Ab's causes OPCs excitotoxicity, and the underlying mechanisms remain unclear. In this study, we found that the survival rate of OPCs decreased, apoptosis increased and the release of LDH increased with GluR3B Ab's treatment. GluR3B Ab's enhanced the level of intracellular Ca2+ and reactive oxygen species (ROS), caused mitochondrial potential collapse measured by JC-1 and promoted mitochondrial cytochrome C release. AMPARs antagonist NBQX reversed OPCs apoptosis caused by GluR3B Ab's. Taken together, these data suggests that AMPAR was involved in GluR3B Ab's-induced OPCs toxicity by mitochondrial dysfunction. The study revealed a new mechanism for OPCs excitotoxicity in many central nervous system diseases such as epilepsy.
Subject(s)
Mitochondria/immunology , Oligodendrocyte Precursor Cells/immunology , Oligodendrocyte Precursor Cells/physiology , Receptors, AMPA/immunology , Animals , Apoptosis , Autoantibodies , Calcium/metabolism , Cell Survival , Cells, Cultured , Mitochondria/metabolism , Rats, Sprague-Dawley , Reactive Oxygen SpeciesABSTRACT
The Sox family of HMG (high mobility group)-box transcription factors are highly conserved in vertebrates. Sox members are involved in various developmental processes. Among them Sox17 has been demonstrated to function as an endoderm determinant in zebrafish and Xenopus, respectively. However, little is known about the role of Sox17 in mouse embryonic stem cell (ESC) differentiation. In our research, we investigated the effect of Sox17 on mouse ESC and embryoid body (EB) differentiation. The results demonstrated that Sox17 overexpression upregulated a set of endoderm-specific gene markers, suggesting that Sox17 overexpression induced an ESC differentiation program towards both primitive and definitive endoderm. We believe this finding brings new insights into the understanding of ESC differentiation and the organogenesis of endodermal derivatives.
