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Candidate pathways for promoting differentiation and quiescence of oligodendrocyte progenitor-like cells in glioblastoma

ABSTRACT: The mature CNS contains PDGFRA+ ‘oligodendrocyte progenitor cells’ (OPC) which may remain quiescent, proliferate, or differentiate into oligodendrocytes. In human gliomas, rapidly proliferating Olig2+ cells resembling OPCs are frequently observed. We sought to identify, in vivo, candidate pathways uniquely required for OPC differentiation or quiescence. Using the bacTRAP methodology, we generated and analyzed mouse lines for translational profiling the major cells types (including OPCs), in the normal mouse brain. We then profiled oligodendoglial (Olig2+) cells from a mouse model of Pdgf-driven glioma. This analysis confirmed that Olig2+ tumor cells are most similar to OPCs, yet, it identified differences in key progenitor genes - candidates for promotion of differentiation or quiescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE30626 | GEO | 2012/10/04

SECONDARY ACCESSION(S): PRJNA144543

REPOSITORIES: GEO

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Candidate pathways for promoting differentiation and quiescence of oligodendrocyte progenitor-like cells in glioblastoma

Project description:The mature CNS contains PDGFRA+ ‘oligodendrocyte progenitor cells’ (OPC) which may remain quiescent, proliferate, or differentiate into oligodendrocytes. In human gliomas, rapidly proliferating Olig2+ cells resembling OPCs are frequently observed. We sought to identify, in vivo, candidate pathways uniquely required for OPC differentiation or quiescence. Using the bacTRAP methodology, we generated and analyzed mouse lines for translational profiling the major cells types (including OPCs), in the normal mouse brain. We then profiled oligodendoglial (Olig2+) cells from a mouse model of Pdgf-driven glioma. This analysis confirmed that Olig2+ tumor cells are most similar to OPCs, yet, it identified differences in key progenitor genes - candidates for promotion of differentiation or quiescence. There are two datasets here. One characterizes the normal translational profiles of neurons, astrocytes, mature and immature oligodendrocytes. Each cell type was profiled in triplicate, from pools of at least two mice, and total RNA controls were collected in parallel. The second dataset includes translational profiles of Olig2 positive cells from tumors form several variations of a murine model of glioma. Each variation was collected at least in triplicate, and total RNA controls were analyzed in parallel. All translational profiles were generated using the Translating Ribosome Affinity Purification protocol.

2012-10-04 | E-GEOD-30626 | biostudies-arrayexpress

Rapid differentiation of hiPSCs into functional oligodendrocytes using an OLIG2 synthetic modified messenger RNARapid differentiation of hiPSCs into functional oligodendrocytes using an OLIG2 synthetic modified messenger RNA

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2023-03-10 | PXD036975 | Pride

Project description:Human oligodendrocyte progenitor cells (hOPCs) persist into adulthood as an abundant precursor population of capable of division and differentiation. The transcriptional mechanisms that regulate hOPC homeostasis remain poorly defined. Herein, we identified paired related homeobox protein 1 (PRRX1) in primary PDGFaR+ hOPCs. We show that enforced PRRX1 expression resulted in reversible G0/1 arrest. While both PRRX1 splice variants reduced hOPC proliferation, only PRRX1a abrogated migration. hOPCs engraftment into hypomyelinated shiverer/rag2 mouse brain was severely impaired by PRRX1a, characterized by reduced cell proliferation and migration. PRRX1 induced a gene expression signature characteristic of stem cell quiescence. Both IFN-g and BMP signaling up-regulated PRRX1 and induced quiescence. Importantly, PRRX1 knockdown modulated IFN-g induced quiescence. In mouse brain, PRRX1 mRNA was detected in non-dividing OPCs and was up-regulated in OPCs following demyelination. Together, these data identify PRRX1 as a regulator of quiescence in hOPCs and as a potential regulator of pathological quiescence.

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2013-04-23 | E-GEOD-40676 | biostudies-arrayexpress

Changes in the oligodendrocyte cell progenitor cell proteome with ageing

Project description:Following CNS demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. While remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis on OPCs isolated acutely from the brains of neonate, young and aged female rats. Approximately 60% of the proteins are expressed at different levels in OPCs from neonates compared to their adult counterparts. The amount of myelin-associated and cell adhesion proteins are increased with age, while cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC rodent proteome, revealing the distinct features of neonatal and adult OPCs, and providing new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

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Changes in the oligodendrocyte cell progenitor cell proteome with ageing

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Transcriptional profiling of murine oligodendrocyte precursor cells across the lifespan

Project description:Oligodendrocyte progenitor cells (OPCs) are highly dynamic, abundant glial cells of the central nervous system (CNS) that are responsible for generating myelinating oligodendrocytes during development. OPCs are also mobilized to form new myelin sheaths in the adult CNS in response to environmental and behavioral changes, and play a crucial role in regenerating myelin following demyelination (remyelination). However, the rates of OPC proliferation and differentiation decline dramatically with aging, impairing homeostasis, remyelination, and potentially adaptive myelination during learning. To determine how aging influences OPCs, we generated a novel transgenic mouse line that expresses EGFP under the endogenous promoter/enhancer of Matrilin-4 (Matn4-mEGFP), allowing OPCs to be purified apart from perivascular and mural cells. OPCs isolated from the cerebral cortex of Matn4-mEGFP mice were subjected to single-cell RNA sequencing, providing enhanced resolution of transcriptional changes during key transitions from quiescence to proliferation and differentiation. Comparative analysis of OPCs isolated from mice aged 30 to 720 days, revealed that aging induces distinct inflammatory transcriptomic changes in OPCs in different states, including enhanced activation of HIF-1α and Wnt pathways. Inhibition of these pathways in acutely isolated OPCs from aged mice promoted their differentiation, suggesting that this enhanced signaling may contribute to the decreased regenerative potential of OPCs with aging. This Matn4-mEGFP mouse line and single-cell mRNA datasets of cortical OPCs across ages serve as a valuable reference to help define the molecular changes guiding their behavior in various physiological and pathological contexts.

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CD133/CD140a-Based Isolation of Distinct Human Multipotent Neural Progenitor Cells and Oligodendrocyte Progenitor Cells

2013-04-23 | GSE40676 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M III

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-B overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

2021-10-05 | GSE184936 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M II

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

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