Francesca Fagiani, Edoardo Pedrini, Stefano Taverna, Elena Brambilla, Valentina Murtaj, Paola Podini, Francesca Ruffini, Erica Butti, Clarissa Braccia, Annapaola Andolfo, Roberta Magliozzi, Lena Smirnova, Tanja Kuhlmann, Angelo Quattrini, Peter A Calabresi, Daniel S Reich, Gianvito Martino, Paola Panina-Bordignon, Martina Absinta
{"title":"胶质丰富的干细胞三维人脑模型模拟了多发性硬化症的胶质-免疫神经退行性表型。","authors":"Francesca Fagiani, Edoardo Pedrini, Stefano Taverna, Elena Brambilla, Valentina Murtaj, Paola Podini, Francesca Ruffini, Erica Butti, Clarissa Braccia, Annapaola Andolfo, Roberta Magliozzi, Lena Smirnova, Tanja Kuhlmann, Angelo Quattrini, Peter A Calabresi, Daniel S Reich, Gianvito Martino, Paola Panina-Bordignon, Martina Absinta","doi":"10.1016/j.xcrm.2024.101680","DOIUrl":null,"url":null,"abstract":"<p><p>The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7000,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.\",\"authors\":\"Francesca Fagiani, Edoardo Pedrini, Stefano Taverna, Elena Brambilla, Valentina Murtaj, Paola Podini, Francesca Ruffini, Erica Butti, Clarissa Braccia, Annapaola Andolfo, Roberta Magliozzi, Lena Smirnova, Tanja Kuhlmann, Angelo Quattrini, Peter A Calabresi, Daniel S Reich, Gianvito Martino, Paola Panina-Bordignon, Martina Absinta\",\"doi\":\"10.1016/j.xcrm.2024.101680\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. 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A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.
The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.
Cell Reports MedicineBiochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍:
Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine.
Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.