Multiple sclerosis

Publication date: 20/08/2024

Authors: Fagiani, Pedrini, Taverna, Brambilla, Murtaj, Podini, Ruffini, Butti, Braccia, Andolfo, Magliozzi, Smirnova, Kuhlmann, Quattrini, Calabresi, Reich, Martino, Panina-Bordignon, Absinta

Journal: Cell Reports Medicine

Commentary: This study provides an innovative and well-validated human stem cell-based platform that overcomes several limitations of current multiple sclerosis (MS) models. A major strength is the development of glia-enriched organoids through transient SOX10 overexpression, which markedly accelerates oligodendrocyte differentiation, allowing the generation of mature MBP-positive oligodendrocytes within only eight weeks. Single-cell RNA sequencing demonstrated that these organoids contain a diverse repertoire of mature neurons, astrocytes, oligodendrocytes, and iPSC-derived microglia, with transcriptional profiles closely resembling those of the adult human brain, thus representing a substantial improvement over conventional cortical organoids. The translational relevance of the model is convincingly demonstrated by exposing organoids to inflammatory cerebrospinal fluid (CSF) from patients with MS. This approach reproduced key pathological features of chronic active lesions, including rapid activation of microglia and astrocytes, induction of inflammatory pathways, antigen presentation, complement signaling, and oxidative stress responses. Particularly noteworthy is the observation that CSF-exposed microglia acquired transcriptional signatures highly overlapping with the MIMS-iron phenotype previously identified in chronic active MS lesions, including upregulation of SPP1, HLA-DRA, FTH1, FTL, and inflammatory cytokine-related genes. In parallel, oligodendrocytes and oligodendrocyte precursor cells exhibited marked vulnerability, characterized by translational dysfunction, induction of GPR17, and activation of TNFα/NF-κB signaling. These molecular alterations translated into a nearly 50% reduction in mature oligodendrocytes after six days of CSF exposure, whereas neuronal survival remained largely preserved, supporting the concept that glial dysfunction precedes overt neurodegeneration in progressive MS. Overall, this work provides compelling mechanistic evidence that soluble inflammatory mediators present in the CSF are sufficient to trigger disease-relevant glial interactions and oligodendrocyte loss. By faithfully reproducing critical aspects of chronic compartmentalized inflammation, this organoid platform represents a powerful tool for investigating the cellular mechanisms driving progressive MS and offers a highly promising system for the preclinical screening of remyelinating and neuroprotective therapies.

Commented by: Ramona Meanti

DOI: https://doi.org/10.1016/j.xcrm.2024.101680