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.
Authors
- Martina Absinta (ORCID: https://orcid.org/0000-0003-0276-383X)
- Annapaola Andolfo (ORCID: https://orcid.org/0000-0002-0566-2391)
- Edoardo Pedrini (ORCID: https://orcid.org/0000-0002-2813-9261)
- Gianvito Martino (ORCID: https://orcid.org/0000-0003-1295-9131)
- Angelo Quattrini (ORCID: https://orcid.org/0000-0002-8226-8320)
- Francesca Fagiani (ORCID: https://orcid.org/0000-0001-7722-0624)
- Daniel S. Reich (ORCID: https://orcid.org/0000-0002-2628-4334)
- Francesca Ruffini (ORCID: https://orcid.org/0000-0002-2226-6366)
- Paola Panina‐Bordignon (ORCID: https://orcid.org/0000-0001-9913-8568)
- Paola Podini (ORCID: https://orcid.org/0000-0002-4757-9887)
- Valentina Murtaj (ORCID: https://orcid.org/0000-0003-0498-1478)
- Clarissa Braccia (ORCID: https://orcid.org/0000-0002-6343-9614)
- Tanja Kuhlmann (ORCID: https://orcid.org/0000-0002-0174-5042)
- Peter A. Calabresi (ORCID: https://orcid.org/0000-0002-7776-6472)
- Stefano Taverna (ORCID: https://orcid.org/0000-0003-1871-8662)
- Roberta Magliozzi (ORCID: https://orcid.org/0000-0001-8284-7763)
- Erica Butti (ORCID: https://orcid.org/0000-0003-0362-273X)
- Lena Smirnova (ORCID: https://orcid.org/0000-0003-0171-3881)
- Elena Brambilla (ORCID: https://orcid.org/0000-0003-1399-2128)
Institutions
- University of Verona (IT)
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Vita-Salute San Raffaele University (IT)
- University Hospital Münster (DE)
- National Institute of Neurological Disorders and Stroke (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101680
- Citations
- 28
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 6.93
Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- International Progressive MS Alliance
- Fondazione Cariplo
- Fondazione Regionale per la Ricerca Biomedica
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke