RNA-seq analysis of human iPSC-derived oligodendrocytes cultured on nanofibers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE327118 | GEO | 2026/06/18
REPOSITORIES: GEO
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Project description:RNA-seq analysis of human iPSC-derived oligodendrocytes cultured on nanofibers
| PRJNA1449474 | ENA
Project description:We engineered a novel human iPSC-derived organoid system enriched with mature, myelinating oligodendrocytes and functionally reactive microglia. This model enables the study of human CNS remyelination following a demyelinating insult, encapsulating: myelin fragmentation, microglial clearance of myelin debris and oligodendrocyte genesis, differentiation, and axon ensheathment. This system provides a powerful and unparalleled capacity to interrogate complex human cell behaviour, relevant to those studying glial biology and neurological disease mechanisms.
2025-07-28 | GSE303406 | GEO
Project description:Claudin 11 (CLDN11) is a member of the claudin family. Claudins are cell-cell adhesion molecules situated at tight junctions. The claudin family in mammals comprises 27 four-transmembrane domain proteins. Therein, cerebral CLDN11 is concentrated in oligodendrocytes and its dysregulation has been documented in several CNS disorders. We found that the expression of CLDN11 was significantly upregulated in oligodendrocytes of epileptic patients. To clarify the role of CLDN11 in oligodendrocytes in epileptic pathology, we transfected the human iPSC-derived oligodendrocytes with CLDN11 plasmid or vector control plasmid for 48 hours, respectively. Subsequently, three CLDN11-overexpressing and three vector control human iPSC-derived oligodendrocyte samples were subject to RNA sequencing.
2024-08-10 | GSE274180 | GEO
Project description:Increasing evidence indicates heterogeneity in functional and molecular properties of oligodendrocyte lineage cells both during development and under pathologic conditions. In multiple sclerosis, remyelination of grey matter lesions exceeds that in white matter. Here we used cells derived from grey matter versus white matter regions of surgically resected human brain tissue samples, to compare the capacities of human A2B5-positive progenitor cells and mature oligodendrocytes to ensheath synthetic nanofibers, and relate differences to the molecular profiles of these cells. For both cell types, the percentage of ensheathing cells was greater for grey matter versus white matter cells. For both grey matter and white matter samples, the percentage of cells ensheathing nanofibers was greater for A2B5-positive cells versus mature oligodendrocytes. Grey matter A2B5-positive cells were more susceptible than white matter A2B5-positive cells to injury induced by metabolic insults. Bulk RNA sequencing indicated that separation by cell type (A2B5-positive vs mature oligodendrocytes) is more significant than by region but segregation for each cell type by region is apparent. Molecular features of grey matter versus white matter derived A2B5-positive and mature oligodendrocytes were lower expression of mature oligodendrocyte genes and increased expression of early oligodendrocyte lineage genes. Genes and pathways with increased expression in grey matter derived cells with relevance for myelination included those related to responses to external environment, cell-cell communication, cell migration, and cell adhesion. Immune and cell death related genes were up-regulated in grey matter derived cells. We observed a significant number of up-regulated genes shared between the stress/injury and myelination processes, providing a basis for these features. In contrast to oligodendrocyte lineage cells, no functional or molecular heterogeneity was detected in microglia maintained in vitro, likely reflecting the plasticity of these cells ex vivo. The combined functional and molecular data indicate that grey matter human oligodendrocytes have increased intrinsic capacity to myelinate but also increased injury susceptibility, in part reflecting their being at a stage earlier in the oligodendrocyte lineage.
2024-11-08 | GSE281006 | GEO
Project description:Transcriptional abnormalities in iPSC-derived oligodendrocytes of individuals with primary progressive multiple sclerosis
| PRJNA871916 | ENA
Project description:Failure of oligodendrocytes to remyelinate underlies diseases such as multiple sclerosis (MS). We found that epigenetic silencing prevents oligodendrocytes from producing myelin sheaths in demyelinating MS lesions. Here, we developed a transgenic reporter system to identify a small-molecule epigenetic modulator that stimulates oligodendrocyte maturation and myelin ensheathment in vitro. This compound promoted remyelination in animal models of MS and myelination of regenerated axons and increased myelin sheath lengths in human iPSC-derived organoids. Multi-omics analyses revealed that the compound induced an enhancer/super-enhancer landscape that upregulates crucial myelinogenesis-associated pathways, including RRAS2-AKT signaling, driving actin depolymerization necessary for myelin ensheathment. Strikingly, the compound also induced phase-separated nuclear condensates of SREBP1/2, which concentrate transcriptional co-activators to drive lipid and cholesterol biosynthesis. Silencing expression of a potential target of the small molecule, HDAC3, facilitated robust myelination and remyelination. Our findings suggest that small-molecule-modulated epigenome rejuvenation relieves epigenetic silencing barriers and promotes myelin repair.
2024-05-24 | GSE232954 | GEO
Project description:Failure of oligodendrocytes to remyelinate underlies diseases such as multiple sclerosis (MS). We found that epigenetic silencing prevents oligodendrocytes from producing myelin sheaths in demyelinating MS lesions. Here, we developed a transgenic reporter system to identify a small-molecule epigenetic modulator that stimulates oligodendrocyte maturation and myelin ensheathment in vitro. This compound promoted remyelination in animal models of MS and myelination of regenerated axons and increased myelin sheath lengths in human iPSC-derived organoids. Multi-omics analyses revealed that the compound induced an enhancer/super-enhancer landscape that upregulates crucial myelinogenesis-associated pathways, including RRAS2-AKT signaling, driving actin depolymerization necessary for myelin ensheathment. Strikingly, the compound also induced phase-separated nuclear condensates of SREBP1/2, which concentrate transcriptional co-activators to drive lipid and cholesterol biosynthesis. Silencing expression of a potential target of the small molecule, HDAC3, facilitated robust myelination and remyelination. Our findings suggest that small-molecule-modulated epigenome rejuvenation relieves epigenetic silencing barriers and promotes myelin repair.
2024-05-24 | GSE232953 | GEO
Project description:Failure of oligodendrocytes to remyelinate underlies diseases such as multiple sclerosis (MS). We found that epigenetic silencing prevents oligodendrocytes from producing myelin sheaths in demyelinating MS lesions. Here, we developed a transgenic reporter system to identify a small-molecule epigenetic modulator that stimulates oligodendrocyte maturation and myelin ensheathment in vitro. This compound promoted remyelination in animal models of MS and myelination of regenerated axons and increased myelin sheath lengths in human iPSC-derived organoids. Multi-omics analyses revealed that the compound induced an enhancer/super-enhancer landscape that upregulates crucial myelinogenesis-associated pathways, including RRAS2-AKT signaling, driving actin depolymerization necessary for myelin ensheathment. Strikingly, the compound also induced phase-separated nuclear condensates of SREBP1/2, which concentrate transcriptional co-activators to drive lipid and cholesterol biosynthesis. Silencing expression of a potential target of the small molecule, HDAC3, facilitated robust myelination and remyelination. Our findings suggest that small-molecule-modulated epigenome rejuvenation relieves epigenetic silencing barriers and promotes myelin repair.
2024-05-24 | GSE232955 | GEO
Project description:In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts and surrounds a selected portion of axon. While a drastic shift to actin depolymerization is then required to enable the wrapping process and the formation of a multilayered myelin sheath. Molecular mechanisms regulating this switch to actin depolymerization are not fully elucidated. P21-activated kinase 1 (PAK1), a downstream effector of Rho GTPases Rac1 and Cdc42, highly expressed in OLs, can regulate actin dynamics through its kinase activity. We found that PAK1 loss-of-function in OLs, in vivo, stimulates the wrapping and the thickening of myelin sheaths. We showed that PAK1 is highly expressed in myelinating OLs, yet in its inactive form, the one with the ability to trigger actin disassembly. Interestingly, we found that modulations of PAK1 kinase activity control actin dynamics in OLs, thereby myelin formation. Our data demonstrate that PAK1 inactivation in OLs is required for actin depolymerization and proper myelin formation, suggesting the presence of an endogenous PAK1 inhibitor in myelinating OLs. Proteomic analysis of PAK1 binding partners enabled us to identify several proteins likely to regulate its activity.
2024-06-03 | PXD044344 | Pride
Project description:Metformin restores myelination potential of aged rat A2B5+ oligodendroglia (OL) progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4+A2B5+) have superior capacity to ensheath nanofibers compared to mature OLs, with cells from pediatric sources exceeding adults. In this study we assessed effects of metformin on ensheathment capacity of human adult and pediatric progenitors and mature OLs and relate differences to transcriptional changes. A2B5+ progenitors and mature OLs, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofiber plates over 2 weeks. Metformin (10µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature OLs. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by pediatric cells. Metformin marginally increased cell death in pediatric progenitors. Metformin induced changes in gene expression distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in process outgrowth and promoting lipid biosynthesis. Pediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development, and synaptic transmission. Metformin induced AMPK activation in all cell types; AMPK inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage related differences of human OL lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate in vivo.
2023-11-11 | GSE247159 | GEO