Oligodendrocyte precursor cells sculpt the visual system by regulating axonal remodeling.
Ontology highlight
ABSTRACT:
SUBMITTER: Xiao Y
PROVIDER: S-EPMC8904260 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Following stroke-induced neuronal damage, quiescent oligodendrocyte precursors (OPCs) are activated to proliferate and later to differentiate to myelin-producing cells. GPR17, a receptor transiently expressed on early OPCs, has emerged as a target to implement stroke repair through stimulation of OPC maturation. However, being GPR17 completely downregulated in myelin-producing oligodendrocytes, its actual role in determining the final fate of OPCs after cerebral ischemia is still uncertain. Here, to univocally define the spatiotemporal changes and final fate of GPR17-expressing OPCs, we induced ischemia by middle cerebral artery occlusion (MCAo) in reporter GPR17iCreERT2:CAG-eGreen florescent protein (GFP) mice, in which, upon tamoxifen treatment, cells expressing GPR17 become green and traceable for their entire life. Starting from 3 days and up to 2 weeks after MCAo, GFP+ cells markedly accumulated in regions surrounding the ischemic lesion; several of them proliferated, as shown by co-labeling of the DNA synthesis marker 5-Bromo-2'-deoxyuridine (BrdU). Almost all GFP+/BrdU+ cells expressed the OPC early marker neural/glial antigen 2 (NG2), indicating that they were still precursors. Accumulation of GFP+ cells was also because of OPC recruitment from surrounding areas, as suggested in vivo by acquisition of typical features of migrating OPCs, shown in vitro in presence of the chemoattractant PDGF-AA and confirmed by transplantation of GFP+-OPCs in wild-type MCAo mice. Eight weeks after MCAo, only some of these precociously recruited cells had undergone maturation as shown by NG2 loss and acquisition of mature myelinating markers like GSTpi. A pool of recruited GFP+-OPCs was kept at a precursor stage to likely make it available for further insults. Thus, very early after ischemia, GFP+-OPCs proliferate and migrate toward the lesion; however, most of these cells remain undifferentiated, suggesting functional roles other than myelination.
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Project description:NG2 protein-expressing oligodendrocyte progenitor cells (OPC) are a persisting and major glial cell population in the adult mammalian brain. Direct synaptic innervation of OPC by neurons throughout the brain together with their ability to sense neuronal network activity raises the question of additional physiological roles of OPC, supplementary to generating myelinating oligodendrocytes. In this study we investigated whether OPC express neuromodulatory factors, typically synthesized by other CNS cell types. Our results show that OPC express two well-characterized neuromodulatory proteins: Prostaglandin D2 synthase (PTGDS) and neuronal Pentraxin 2 (Nptx2/Narp). Expression levels of the enzyme PTGDS are influenced in cultured OPC by the NG2 intracellular region which can be released by cleavage and localizes to glial nuclei upon transfection. Furthermore PTGDS mRNA levels are reduced in OPC from NG2-KO mouse brain compared to WT cells after isolation by cell sorting and direct analysis. These results show that OPC can contribute to the expression of these proteins within the CNS and suggest PTGDS expression as a downstream target of NG2 signaling.
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Project description:Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenous α-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains.
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Project description:Human cerebral cortex size and complexity has increased greatly during evolution. While increased progenitor diversity and enhanced proliferative potential play important roles in human neurogenesis and gray matter expansion, the mechanisms of human oligodendrogenesis and white matter expansion remain largely unknown. Here, we identify EGFR-expressing "Pre-OPCs" that originate from outer radial glial cells (oRGs) and undergo mitotic somal translocation (MST) during division. oRG-derived Pre-OPCs provide an additional source of human cortical oligodendrocyte precursor cells (OPCs) and define a lineage trajectory. We further show that human OPCs undergo consecutive symmetric divisions to exponentially increase the progenitor pool size. Additionally, we find that the OPC-enriched gene, PCDH15, mediates daughter cell repulsion and facilitates proliferation. These findings indicate properties of OPC derivation, proliferation, and dispersion important for human white matter expansion and myelination.
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Project description:Multiple system atrophy is a neurodegenerative disorder characterized pathologically by abnormal accumulations of α-synuclein in the cytoplasm of oligodendrocytes, which are termed glial cytoplasmic inclusions (GCIs). Oligodendrocytes are responsible for myelinating axons and providing neurotrophic support, but in MSA, myelin loss, axonal loss and gliosis are consistent features suggesting that GCIs play a central role in disease pathogenesis. Oligodendroglial, myelin and axonal degeneration are also features of multiple sclerosis (MS) in which recent studies have highlighted the robust remyelination capacity of the central nervous system (CNS). The cells responsible for remyelination are called oligodendroglial precursor cells (OPCs). In this study, we investigated the role of OPCs in the pathogenesis of MSA and progressive supranuclear palsy (PSP), a neurodegenerative disease in which neuropathological changes include oligodendroglial inclusions composed of microtubule-associated protein tau. Despite the lability of OPC-specific antigens, we successfully identified OPCs and demonstrated that tau and α-synuclein do not accumulate in OPCs. We also showed that the density of OPCs was increased in a white matter region of the MSA brain, which is also severely affected by GCIs and myelin degeneration. These findings raise the possibility that OPCs could be available to repair disease-associated damage in MSA, consistent with their biological function.
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Project description:Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination; these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs; as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.
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