Reactive human iPSC astrocytes suppress oligodendrocyte precursor cell differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA805526 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17984700_1.fastq.gz | Fastqsanger.gz | |||
| SRR17984700_2.fastq.gz | Fastqsanger.gz | |||
| SRR17984701_1.fastq.gz | Fastqsanger.gz | |||
| SRR17984701_2.fastq.gz | Fastqsanger.gz | |||
| SRR17984702_1.fastq.gz | Fastqsanger.gz |
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Project description:Astrocytes are instrumental in maintaining central nervous system (CNS) homeostasis and responding to injury. A major limitation of studying neurodegenerative diseases like multiple sclerosis (MS) is lack of human pathological specimens obtained during the acute stages, thereby relegating research to post-mortem specimens obtained years after the initiation of pathology. Rodent reactive astrocytes have been shown to be cytotoxic to neurons and oligodendrocytes but may differ from human cells, especially in diseases with genetic susceptibility. Herein, we purified human CD49f+ astrocytes from induced pluripotent stem cells derived from individual patient and control peripheral leukocytes. We compared TNF and IL1α stimulated human reactive astrocytes from seven persons with MS and six non-MS controls and show their transcriptomes are remarkably similar to those described in rodents. The functional effect of astrocyte conditioned media (ACM) was examined in a human oligodendrocyte precursor cell (OPC) line differentiation assay. ACM was not cytotoxic to the OPCs but robustly inhibited the myelin basic protein (MBP) reporter. No differences were seen between MS and control stimulated astrocytes at either the transcript level or in ACM mediated OPC suppression assays. We next used RNAseq to interrogate differentially expressed genes in the OPC lines that had suppressed differentiation from the human ACM. Remarkably, not only was OPC differentiation and myelin gene expression suppressed, but we observed induction of several immune pathways in OPCs exposed to the ACM. These data support the notion that reactive astrocytes can inhibit OPC differentiation thereby limiting their remyelination capacity, and that OPCs take on an immune profile in the context of inflammatory cues.
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Project description:Reactive astrocytes are implicated in amyotrophic lateral sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human iPSC-derived astrocytes carrying VCP, C9orf72 and SOD1 ALS-causing mutations as well as astrocytes stimulated to undergo reactive transformation. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell-adhesion, stress-response, and immune-activation. We examined translatome sequencing (TRAP-seq) of astrocytes from a SOD1 mouse model, which revealed that transcripts upregulated in translation significantly overlap with transcripts with decreased IR. Using nucleo-cytoplasmic fractionation of VCP astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear-detained transcripts is associated with increased cytoplasmic expression of genes and proteins encoding regulators of reactivity - indicating nuclear-to-cytoplasmic translocation and translation of spliced reactivity-related transcripts. Our study provides important insights into the molecular regulation of reactive transformation of ALS astrocytes.
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