ABSTRACT
Oligodendrocyte precursor cells (OPCs) have long been regarded as progenitors of oligodendrocytes, yet recent advances have illuminated their multifaceted nature including their emerging immune functions. This review seeks to shed light on the immune functions exhibited by OPCs, spanning from phagocytosis to immune modulation and direct engagement with immune cells across various pathological scenarios. Comprehensive understanding of the immune functions of OPCs alongside their other roles will pave the way for targeted therapies in neurological disorders.
Subject(s)
Oligodendrocyte Precursor Cells , Humans , Oligodendrocyte Precursor Cells/immunology , Animals , Phagocytosis/immunology , Oligodendroglia/immunology , Cell Differentiation/immunology , ImmunomodulationABSTRACT
Multiple sclerosis (MS) is a leading cause of chronic neurological dysfunction in young to middle-aged adults, affecting approximately 2.5 million people worldwide. It is characterized by inflammation, multifocal demyelination, axonal loss, and white and gray matter gliosis. Autophagy is a highly conserved protein degradation pathway. Polymorphisms in autophagy-related genes have been implicated in a variety of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, psoriasis and MS. However, the significance of autophagy in MS remains to be elucidated. This paper aims to explore the potential role of autophagy-related genes in MS diseases by using bioinformatics combined with machine learning methods. Finally, we obtained 9 autophagy genes with the highest correlation with MS, and further changes in these autophagy genes were verified in the experimental autoimmune encephalomyelitis (EAE) model and oligodendrocyte precursor cells (OPCs) engulfed myelin debris (MD). Combined with bioinformatic analysis and experimental data, Becn1 showed obvious expression abnormalities suggesting that this gene has vital functions in autophagy and MD engulfed by OPCs. This work will be of great significance for the further exploration of autophagy-related genes in demyelinating diseases.
Subject(s)
Autophagy , Multiple Sclerosis , Oligodendrocyte Precursor Cells , Phagocytosis , Autophagy/genetics , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Phagocytosis/genetics , Oligodendrocyte Precursor Cells/immunology , Computational Biology , Machine Learning , Animals , Mice , Female , Mice, Inbred C57BL , Beclin-1/genetics , Beclin-1/immunology , Gene Expression Profiling , Myelin Sheath/metabolism , Myelin Sheath/pathologyABSTRACT
INTRODUCTION: AQP4 (aquaporin-4)-immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4-IgG in cell differentiation. MATERIAL AND METHODS: We included three groups-a group of patients with AQP4-IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. RESULTS AND CONCLUSIONS: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.
Subject(s)
Aquaporin 4/immunology , Autoantibodies/immunology , Cell Differentiation , Central Nervous System/pathology , Immunoglobulin G/immunology , Neuromyelitis Optica/immunology , Oligodendrocyte Precursor Cells/pathology , Animals , Autoantibodies/blood , Case-Control Studies , Central Nervous System/immunology , Cerebellum/immunology , Cerebellum/pathology , Female , Humans , Male , Mice, Inbred BALB C , Middle Aged , Neuromyelitis Optica/blood , Neuromyelitis Optica/pathology , Oligodendrocyte Precursor Cells/immunologyABSTRACT
Oligodendrocyte precursor cells (OPCs) are not merely a transitory progenitor cell type, but rather a distinct and heterogeneous population of glia with various functions in the developing and adult central nervous system. In this review, we discuss the fate and function of OPCs in the brain beyond their contribution to myelination. OPCs are electrically sensitive, form synapses with neurons, support blood-brain barrier integrity, and mediate neuroinflammation. We explore how sex and age may influence OPC activity, and we review how OPC dysfunction may play a primary role in numerous neurological and neuropsychiatric diseases. Finally, we highlight areas of future research.
Subject(s)
Brain/cytology , Oligodendrocyte Precursor Cells/cytology , Oligodendrocyte Precursor Cells/immunology , Age Factors , Animals , Brain/embryology , Brain/immunology , Brain/metabolism , Electrical Synapses/physiology , Humans , Mental Disorders/pathology , Nervous System Diseases/pathology , Oligodendrocyte Precursor Cells/pathology , Oligodendrocyte Precursor Cells/physiology , Sex FactorsABSTRACT
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.
Subject(s)
CD40 Ligand/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Integrin alpha4/metabolism , Multiple Sclerosis/immunology , Myelin Sheath/metabolism , Adult , Animals , Case-Control Studies , Cell Proliferation , Cells, Cultured , Coculture Techniques , Cytokines/metabolism , Disease Models, Animal , Female , Humans , Lymphocytes/cytology , Lymphocytes/immunology , Male , Mice , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein/adverse effects , Oligodendrocyte Precursor Cells/cytology , Oligodendrocyte Precursor Cells/immunology , Peptide Fragments/adverse effects , RemyelinationABSTRACT
Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.
Subject(s)
Antigens/immunology , Central Nervous System/immunology , Demyelinating Diseases/immunology , Oligodendrocyte Precursor Cells/immunology , Oligodendrocyte Precursor Cells/metabolism , Animals , Antigen-Presenting Cells/immunology , Astrocytes/metabolism , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Caspase 3/metabolism , Caspase 7/metabolism , Cell Differentiation , Central Nervous System/metabolism , Cytokines/genetics , Cytokines/metabolism , Demyelinating Diseases/pathology , Disease Models, Animal , Gene Expression , Histocompatibility Antigens Class I , Humans , Interferon-gamma , Mice , Mice, Inbred C57BL , Mice, Transgenic , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Myelin Sheath/metabolism , Oligodendrocyte Precursor Cells/drug effects , Oligodendrocyte Precursor Cells/pathology , Oligodendroglia/metabolism , Ovalbumin/metabolism , Remyelination/immunology , T-LymphocytesABSTRACT
Spinal cord injury (SCI) has been associated with a dismal prognosis-recovery is not expected, and the most standard interventions have been temporizing measures that do little to mitigate the extent of damage. While advances in surgical and medical techniques have certainly improved this outlook, limitations in functional recovery continue to impede clinically significant improvements. These limitations are dependent on evolving immunological mechanisms that shape the cellular environment at the site of SCI. In this review, we examine these mechanisms, identify relevant cellular components, and discuss emerging treatments in stem cell grafts and adjuvant immunosuppressants that target these pathways. As the field advances, we expect that stem cell grafts and these adjuvant treatments will significantly shift therapeutic approaches to acute SCI with the potential for more promising outcomes.
Subject(s)
Graft Rejection/prevention & control , Graft vs Host Disease/prevention & control , Immunosuppressive Agents/therapeutic use , Induced Pluripotent Stem Cells/transplantation , Oligodendrocyte Precursor Cells/transplantation , Spinal Cord Injuries/therapy , Adjuvants, Immunologic , Allografts , Animals , Basiliximab/therapeutic use , Cells, Cultured , Clinical Trials as Topic , Cyclosporine/therapeutic use , Female , Graft Survival/immunology , Human Embryonic Stem Cells/cytology , Human Embryonic Stem Cells/immunology , Humans , Induced Pluripotent Stem Cells/immunology , Male , Mice , Mycophenolic Acid/therapeutic use , Oligodendrocyte Precursor Cells/immunology , Rats , Tacrolimus/therapeutic use , Transplantation, AutologousABSTRACT
Efficient myelin regeneration in the central nervous system (CNS) requires the migration, proliferation and differentiation of oligodendrocyte progenitor cells (OPC) into myelinating oligodendrocytes. In demyelinating diseases such as multiple sclerosis (MS), this regenerative process can fail, and therapies targeting myelin repair are currently completely lacking in the clinic. The immune system is emerging as a key regenerative player in many tissues, such as muscle and heart. We recently reported that regulatory T cells (Treg) are required for efficient CNS remyelination. Furthermore, Treg secrete CCN3, a matricellular protein from the CCN family, implicated in regeneration of other tissues. Treg-derived CCN3 promoted oligodendrocyte differentiation and myelination. In contrast, previous studies showed that CCN2 inhibited myelination. These studies highlight the need for further scrutiny of the roles that CCN proteins play in myelin development and regeneration. Collectively, these findings open up exciting avenues of research to uncover the regenerative potential of the adaptive immune system.
Subject(s)
CCN Intercellular Signaling Proteins/immunology , Central Nervous System/immunology , Myelin Sheath/immunology , Nerve Regeneration/physiology , Remyelination/physiology , T-Lymphocytes, Regulatory/immunology , Animals , CCN Intercellular Signaling Proteins/metabolism , Cell Differentiation/physiology , Central Nervous System/cytology , Central Nervous System/metabolism , Humans , Myelin Sheath/metabolism , Oligodendrocyte Precursor Cells/immunology , Oligodendrocyte Precursor Cells/metabolism , T-Lymphocytes, Regulatory/metabolismABSTRACT
Remyelination following myelin/oligodendrocyte injury in the central nervous system (CNS) is dependent on oligodendrocyte progenitor cells (OPCs) migrating into lesion sites, differentiating into myelinating oligodendrocytes (OLs), and ensheathing axons. Experimental models indicate that robust OPC-dependent remyelination can occur in the CNS; in contrast, histologic and imaging studies of lesions in the human disease multiple sclerosis (MS) indicate the variable extent of this response, which is particularly limited in more chronic MS lesions. Immune-mediated mechanisms can contribute either positively or negatively to the presence and functional responses of OPCs. This review addresses i) the molecular signature and functional properties of OPCs in the adult human brain; ii) the status (presence and function) of OPCs in MS lesions; iii) experimental models and in vitro data highlighting the contribution of adaptive and innate immune constituents to OPC injury and remyelination; and iv) effects of MS-directed immunotherapies on OPCs, either directly or indirectly via effects on specific immune constituents.
Subject(s)
Brain/cytology , Oligodendrocyte Precursor Cells/immunology , Adaptive Immunity , Adult , Animals , Antigens, Differentiation/analysis , Cell Differentiation , Cells, Cultured , Glucose/pharmacology , Humans , Immunity, Innate , Immunotherapy , Mice , Multiple Sclerosis/pathology , Multiple Sclerosis/therapy , Nerve Tissue Proteins/analysis , Neuroimmunomodulation , Oligodendrocyte Precursor Cells/cytology , Oligodendrocyte Precursor Cells/drug effects , Oligodendrocyte Precursor Cells/physiology , Oligodendroglia/cytology , Rats , Remyelination/physiologyABSTRACT
Cerebral white matter injury (WMI) persistently disrupts myelin regeneration by oligodendrocyte progenitor cells (OPCs). We identified a specific bioactive hyaluronan fragment (bHAf) that downregulates myelin gene expression and chronically blocks OPC maturation and myelination via a tolerance-like mechanism that dysregulates pro-myelination signaling via AKT. Desensitization of AKT occurs via TLR4 but not TLR2 or CD44. OPC differentiation was selectively blocked by bHAf in a maturation-dependent fashion at the late OPC (preOL) stage by a noncanonical TLR4/TRIF pathway that induced persistent activation of the FoxO3 transcription factor downstream of AKT. Activated FoxO3 selectively localized to oligodendrocyte lineage cells in white matter lesions from human preterm neonates and adults with multiple sclerosis. FoxO3 constraint of OPC maturation was bHAf dependent, and involved interactions at the FoxO3 and MBP promoters with the chromatin remodeling factor Brg1 and the transcription factor Olig2, which regulate OPC differentiation. WMI has adapted an immune tolerance-like mechanism whereby persistent engagement of TLR4 by bHAf promotes an OPC niche at the expense of myelination by engaging a FoxO3 signaling pathway that chronically constrains OPC differentiation.
Subject(s)
Forkhead Box Protein O3/immunology , Immune Tolerance , Oligodendrocyte Precursor Cells/immunology , Proto-Oncogene Proteins c-akt/immunology , Signal Transduction/immunology , Toll-Like Receptors/immunology , Animals , DNA Helicases/genetics , DNA Helicases/immunology , Female , Forkhead Box Protein O3/genetics , Humans , Mice , Mice, Knockout , Neuregulin-1/genetics , Neuregulin-1/immunology , Nuclear Proteins/genetics , Nuclear Proteins/immunology , Oligodendrocyte Precursor Cells/pathology , Oligodendrocyte Transcription Factor 2/genetics , Oligodendrocyte Transcription Factor 2/immunology , Proto-Oncogene Proteins c-akt/genetics , Rats , Rats, Sprague-Dawley , Signal Transduction/genetics , Toll-Like Receptors/genetics , Transcription Factors/genetics , Transcription Factors/immunologyABSTRACT
Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-α and lipopolysaccaride (LPS). TNF-α time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-α and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-α or LPS challenge, being higher in microglia with TNF-α and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/ neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-α treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS.
Subject(s)
Astrocytes/immunology , Microglia/immunology , Serum Amyloid A Protein/metabolism , Tumor Necrosis Factor-alpha/immunology , Acute-Phase Reaction/immunology , Animals , Cells, Cultured , Humans , Lipopolysaccharides/immunology , Oligodendrocyte Precursor Cells/immunology , RNA, Messenger/genetics , Rats , Up-RegulationABSTRACT
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.