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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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.874299/full |
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| author | Matthew D. Smith Xitiz Chamling Alexander J. Gill Hector Martinez Weifeng Li Weifeng Li Kathryn C. Fitzgerald Elias S. Sotirchos Dorota Moroziewicz Lauren Bauer Daniel Paull Marjan Gharagozloo Pavan Bhargava Donald J. Zack Donald J. Zack Donald J. Zack Donald J. Zack Valentina Fossati Peter A. Calabresi Peter A. Calabresi Peter A. Calabresi |
| author_facet | Matthew D. Smith Xitiz Chamling Alexander J. Gill Hector Martinez Weifeng Li Weifeng Li Kathryn C. Fitzgerald Elias S. Sotirchos Dorota Moroziewicz Lauren Bauer Daniel Paull Marjan Gharagozloo Pavan Bhargava Donald J. Zack Donald J. Zack Donald J. Zack Donald J. Zack Valentina Fossati Peter A. Calabresi Peter A. Calabresi Peter A. Calabresi |
| author_sort | Matthew D. Smith |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-10T05:02:54Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-10T05:02:54Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-5803ad7471a74cfb84d0c6510afbb2422022-12-22T02:01:20ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-05-011510.3389/fnmol.2022.874299874299Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell DifferentiationMatthew D. Smith0Xitiz Chamling1Alexander J. Gill2Hector Martinez3Weifeng Li4Weifeng Li5Kathryn C. Fitzgerald6Elias S. Sotirchos7Dorota Moroziewicz8Lauren Bauer9Daniel Paull10Marjan Gharagozloo11Pavan Bhargava12Donald J. Zack13Donald J. Zack14Donald J. Zack15Donald J. Zack16Valentina Fossati17Peter A. Calabresi18Peter A. Calabresi19Peter A. Calabresi20Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesThe New York Stem Cell Foundation Research Institute, New York, NY, United StatesThe New York Stem Cell Foundation Research Institute, New York, NY, United StatesDepartment of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesThe New York Stem Cell Foundation Research Institute, New York, NY, United StatesThe New York Stem Cell Foundation Research Institute, New York, NY, United StatesThe New York Stem Cell Foundation Research Institute, New York, NY, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesSolomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesThe New York Stem Cell Foundation Research Institute, New York, NY, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesSolomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesAstrocytes 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.https://www.frontiersin.org/articles/10.3389/fnmol.2022.874299/fullmultiple sclerosisastrocyteoligodendrocyteneurotoxicityinduced pluripotent stem cell (iPSC) |
| spellingShingle | Matthew D. Smith Xitiz Chamling Alexander J. Gill Hector Martinez Weifeng Li Weifeng Li Kathryn C. Fitzgerald Elias S. Sotirchos Dorota Moroziewicz Lauren Bauer Daniel Paull Marjan Gharagozloo Pavan Bhargava Donald J. Zack Donald J. Zack Donald J. Zack Donald J. Zack Valentina Fossati Peter A. Calabresi Peter A. Calabresi Peter A. Calabresi Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation Frontiers in Molecular Neuroscience multiple sclerosis astrocyte oligodendrocyte neurotoxicity induced pluripotent stem cell (iPSC) |
| title | Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation |
| title_full | Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation |
| title_fullStr | Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation |
| title_full_unstemmed | Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation |
| title_short | Reactive Astrocytes Derived From Human Induced Pluripotent Stem Cells Suppress Oligodendrocyte Precursor Cell Differentiation |
| title_sort | reactive astrocytes derived from human induced pluripotent stem cells suppress oligodendrocyte precursor cell differentiation |
| topic | multiple sclerosis astrocyte oligodendrocyte neurotoxicity induced pluripotent stem cell (iPSC) |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.874299/full |
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