Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation

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 t...

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Veröffentlicht in:Frontiers in molecular neuroscience Jg. 15; S. 874299
Hauptverfasser: Smith, Matthew D., Chamling, Xitiz, Gill, Alexander J., Martinez, Hector, Li, Weifeng, Fitzgerald, Kathryn C., Sotirchos, Elias S., Moroziewicz, Dorota, Bauer, Lauren, Paull, Daniel, Gharagozloo, Marjan, Bhargava, Pavan, Zack, Donald J., Fossati, Valentina, Calabresi, Peter A.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland Frontiers Research Foundation 06.05.2022
Frontiers Media S.A
Schlagworte:
Alzheimer's disease
astrocyte
Astrocytes
Cell differentiation
Cytokines
Cytotoxicity
Gene expression
Genotype & phenotype
Glial stem cells
Homeostasis
induced pluripotent stem cell (iPSC)
Inflammation
Interleukin 1
Leukocytes
Molecular Neuroscience
Multiple sclerosis
Myelin
Myelination
Nervous system
Neurodegeneration
Neurodegenerative diseases
Neurotoxicity
oligodendrocyte
Oligodendrocytes
Ontology
Pluripotency
Principal components analysis
Stem cell transplantation
Stem cells
Transcription
Transcriptomes
Tumor necrosis factor
induced pluripotent stem cell (iPSC)
neurotoxicity
astrocyte
multiple sclerosis
oligodendrocyte
ISSN:1662-5099, 1662-5099
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Zusammenfassung: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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Reviewed by: Stephen Crocker, University of Connecticut Health Center, United States; John R. Lukens, University of Virginia, United States
Edited by: Amit K. Srivastava, Thomas Jefferson University, United States
This article was submitted to Molecular Signalling and Pathways, a section of the journal Frontiers in Molecular Neuroscience
ISSN:1662-5099
1662-5099
DOI:10.3389/fnmol.2022.874299