RNA-Sequencing reveals mechanisms by which human glial progenitor cells (hGPCs) initiate remyelination
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA448175 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6921500_1.fastq.gz | Fastqsanger.gz | |||
| SRR6921500_2.fastq.gz | Fastqsanger.gz | |||
| SRR6921501_1.fastq.gz | Fastqsanger.gz | |||
| SRR6921501_2.fastq.gz | Fastqsanger.gz | |||
| SRR6921502_1.fastq.gz | Fastqsanger.gz |
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Project description:To investigate transcriptomic drivers of human myelination, immunodeficient mice were chimerized with fetal derived hGPCs at P1, sacrified at 36 weeks, and hGPCs were extracted for RNA-Sequencing via FACS. Mice were either fed a control diet for the entireity of their lives or a demyelinating diet beginning at 12 weeks of age until 24 weeks, when they were transitioned to a control diet to allow for remyelination to begin.
2020-05-09 | GSE112557 | GEO
Project description:Glial progenitor cells comprise the most abundant population of progenitor cells in the adult human brain. They are responsible for CNS remyelination, and likely contribute to the astrogliotic response to brain injury and degeneration as well. Adult human GPCs are biased to differentiate as oligodendrocytes and elaborate new myelin, and yet they retain multilineage plasticity, and can give rise to neurons as well as astrocytes and oligodendrocytes once removed from the adult parenchymal environment. GPCs retain strong mechanisms for cell-autonomous self-renewal, and yet both their phenotype and fate may be dictated by their microenvironment. Using the transcriptional profiles of acutely isolated GPCs, we have begun to understand the operative ligand-receptor interactions involved in these processes, and have identified several key signaling pathways by which adult human GPCs may be reliably instructed to either oligodendrocytic or astrocytic fate. In addition, we have noted significant differences between the expressed genes and dominant signaling pathways of fetal and adult human GPCs, as well as between rodent and human GPCs. The latter data in particular call into question therapeutic strategies predicated solely upon data obtained using rodents, while perhaps highlighting the extent to which evolution has been attended by the phylogenetic modification of glial phenotype and function. Human adult brain dissociates were sorted for one of three markers, either GLT1 (astrocyte, n =3), CD11b (microglia, n=4) or A2B5 (glial progenitor cell, n=7). In addition to positively selected, the negative fraction and unsorted dissociates were collected as matched controls for each sort.
2012-11-01 | E-GEOD-36634 | biostudies-arrayexpress
Project description:Remyelination failure contributes to axonal dysfunction in neurodegenerative disorders. But whether astrocytes, the most abundant glial cell type in demyelinated lesions, support or impede remyelination is controversial. Following focal demyelinated lesions of the mouse corpus callosum induced with the myelin toxin lysolecithin, we used TRAP (translational ribosome affinity purification) sequencing to isolate and sequence ribosome-associated mRNAs which are being actively translated in astrocytes, and studied how the responses and molecular mechanisms in astrocytes are linked to remyelination.
2023-05-17 | E-MTAB-9270 | biostudies-arrayexpress
Project description:Glial progenitor cells comprise the most abundant population of progenitor cells in the adult human brain. They are responsible for CNS remyelination, and likely contribute to the astrogliotic response to brain injury and degeneration as well. Adult human GPCs are biased to differentiate as oligodendrocytes and elaborate new myelin, and yet they retain multilineage plasticity, and can give rise to neurons as well as astrocytes and oligodendrocytes once removed from the adult parenchymal environment. GPCs retain strong mechanisms for cell-autonomous self-renewal, and yet both their phenotype and fate may be dictated by their microenvironment. Using the transcriptional profiles of acutely isolated GPCs, we have begun to understand the operative ligand-receptor interactions involved in these processes, and have identified several key signaling pathways by which adult human GPCs may be reliably instructed to either oligodendrocytic or astrocytic fate. In addition, we have noted significant differences between the expressed genes and dominant signaling pathways of fetal and adult human GPCs, as well as between rodent and human GPCs. The latter data in particular call into question therapeutic strategies predicated solely upon data obtained using rodents, while perhaps highlighting the extent to which evolution has been attended by the phylogenetic modification of glial phenotype and function.
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Project description:In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet improvable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of ‘improved’ OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edited human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplanted them into rodent models of chronic lesions. Edited hOPCs displayed enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. This study demonstrates that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.
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Project description:Heterogeneity of the human glial progenitor cells
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Project description:Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from primary progressive multiple sclerosis (PPMS) patient induced pluripotent stem (iPS) cell lines failed to promote oligodendrocyte progenitor cell (OPC) maturation whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS autopsy brain tissues and PPMS patient iPS-derived NPCs. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin which then enhanced PPMS NPC support for oligodendrocyte differentiation. A proteomic analysis of the PPMS NPC secretome identified high mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of oligodendrocyte differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in progressive MS which may impact how this disease is modeled and inform development of future myelin regeneration strategies.
2019-11-12 | PXD013060 | Pride
Project description:The goals of this research are three-fold: (i) One is to identify genetic changes associated with tumorgenesis that interfere with the ability of transformed glial cells to differentiate. This is connected with (ii) our analysis of the regulation of differentiation in normal glial progentor cells, as only by understanding this in normal cells can we understand what is occurring when differentiation fails in transformed versions of the same cells. (iii) The third is to identify the molecular basis for the greater resistance of transformed glial progenitor cells to chemotherapeutic agents as compared with normal glial progenitor cells. Thus, analysis of the populations provided will yield data crucial to two of our central areas of research, as awarded by NINDS in "Oligodendrocytes & precursors: toxicity of chemotherapy" (5R01NS044701), and "Low-level toxicant perturbation of neural cell function" (1R01ES012708). Our ability to work with essentially unlimited numbers of primary progenitor cells and transformed derivatives of these cells offers one of the few systems in which side-by-side comparison of normal and transformed cells at both the biochemical and molecular levels is possible. Using defined cell populations, expression profiles will be compared to reveal changes in cell type specific markers and regulatory factors associated with transformation. In addition, retention of markers despite transformation may enable identification of new markers useful in the diagnosis of glial tumors. Transformation of glial progenitor cells is associated both with loss of the proteins required for normal differentiation and with an inability to normally activate proteins that function in differentiation control. By side-by-side analysis of gene expression in normal and transformed glial progenitor cells, and analysis of the response to inducers of differentiation in each these populations, we will identify candidate regulators critical in the control of normal differentiation. Identification of these regulators will also provide clues as to overcome the blockade of differentiation that occurs in glial cancers (which represent the majority of adult brain tumors). RNA will be isolated from two separate preparations of glial progenitors. Preparation of purified populations has been described in multiple of our previous publications (Mayer, M. et al. (1994) Development 120, 142-153; Mayer-Pröschel, M. et al. (1997) Neuron 19, 773-785; Rao, M. and Mayer-Pröschel, M. (1997) Dev. Biology 188, 48-63). Total RNA from purified cell cultures will be extracted in a two step process. RNA will first be extracted by dounce homogenization in phenol/guanidine isothiocyonate solution (Trizol, Invitrogen, California) followed by isopropanol precipitation. Contaminating traces of DNA and protein will then be removed by silica-based affinity chromatography and Dnase treatment (NucleoSpin RNA Purification system, Clontech, California). Depending on the cell type, 5x105 cells will typically yield 5-15µg of high quality RNA (OD260/280=2.1 at pH7.5). In order to determine purity and molecular weight distribution, samples will be routinely tested on a Agilent Bioanalyzer. cDNA will be generated from total RNA and then be submitted to one round of amplification and labeling using the messageAmp system (Ambion). Probes are then hybridized to the Affymerix Rat 230 (A/B or 2.0) GeneChip expression array. Array data will be processed using the Micro Array Suite 5.0 (MAS, Affymetrix). .Cel files containing normalized, relative expression data for all genes tested will be used for downstream statistical analysis.
2008-06-16 | E-GEOD-9763 | biostudies-arrayexpress
Project description:Extrinsic inhibitors at sites of blood-brain barrier (BBB) disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodeling at site of neurovascular dysfunction are largely unknown. By integrating in vivo two-photon (2P) imaging co-registered with electron microscopy and transcriptomics in chronic neuroinflammatory lesions, we found repressed anticoagulation pathways in oligodendrocyte precursor cells (OPCs) that clustered perivascularly at sites of limited remyelination with deposition of fibrinogen, a blood coagulation factor abundantly deposited in multiple sclerosis lesions. By developing the OPC-X-screen to identify compounds that promote remyelination in the presence of extrinsic inhibitors, we showed that known promyelinating drugs did not rescue extrinsic inhibition of remyelination by fibrinogen. In contrast, bone morphogenetic protein (BMP) receptor blockade rescued the inhibitory fibrinogen effects and restored a promyelinating progenitor niche by promoting myelinating oligodendrocytes, while suppressing astrocyte cell fate with potent therapeutic effects in chronic models of multiple sclerosis. Thus, abortive OPC differentiation by fibrinogen is refractory to known promyelinating compounds, suggesting that blockade of the BMP signaling pathway may enhance remyelinating efficacy by overcoming extrinsic inhibition in neuroinflammatory lesions with vascular damage.
2021-08-24 | GSE166675 | GEO
Project description:Multiple sclerosis (MS) is a chronic, inflammatory condition characterized by demyelination and neurodegeneration. Regeneration of lost myelin, or remyelination, occurs in people with MS but is prone to failure and impaired with age. Remyelination is facilitated by microglia but our understanding of the microglial response during remyelination is incomplete. Here, we profiled the microglial response in the lysolecithin mouse model of remyelination using single-cell RNA sequencing. We found several distinct microglial states during the early stages of remyelination that coalesced into a resolved microglial state defined by myelin transcripts. This resolved state was also present in MS brains. As remyelination becomes inefficient with age, we profiled microglia from both young and middle-aged mice during remyelination and found a delay in several microglial states, in concordance with delayed remyelination. Overall, microglia synchronously initiate a multi-faceted response during efficient remyelination in young mice, which becomes dysregulated with age.
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