新しい4D脳マップが多発性硬化症の初期警告サインを明らかに(New 4D Brain Map Reveals Potential Early Warning Signs of Multiple Sclerosis)

2025-02-27 アメリカ国立衛生研究所 (NIH)

<関連情報>

• https://www.nih.gov/news-events/news-releases/new-4d-brain-map-reveals-potential-early-warning-signs-multiple-sclerosis
• https://www.science.org/doi/10.1126/science.adp6325

マーモセットの4次元脳地図から、多発性硬化症様病変の発症に関するMRIおよび分子シグネチャーが明らかになる 4D marmoset brain map reveals MRI and molecular signatures for onset of multiple sclerosis–like lesions

Jing-Ping Lin, Alexis Brake, Maxime Donadieu, Amanda Lee, […], and Daniel S. Reich
Science  Published:28 Feb 2025

Editor’s summary

Multiple sclerosis (MS) is an immune-mediated disorder characterized by progressive demyelinating brain lesions leading to severe debilitating symptoms. To characterize the spatiotemporal dynamics of demyelination in a translationally relevant primate model of MS (an experimental autoimmune encephalitis marmoset model), Lin et al. performed longitudinal magnetic resonance imaging (MRI)–guided RNA profiling. By correlating MRI-detected lesions with spatial transcriptional changes, the authors identified gene profile microenvironments around the lesions, which enabled them to propose therapeutic targets and potential treatments for MS. —Mattia Maroso

Structured Abstract

INTRODUCTION
Multiple sclerosis (MS) is a complex disease characterized by focal inflammation, myelin loss in the central nervous system, and eventual neurodegeneration. The precise cause of MS remains unclear, but the disease involves an inappropriate immune response and subsequent failure to repair myelin. Although MS therapies have been effective in controlling peripheral inflammation, understanding the cellular dynamics of lesion progression during early phases is crucial for developing treatments that promote timely remyelination and repair.

RATIONALE
Current understanding of MS pathology is largely derived from postmortem human tissue studies or rare brain biopsies, which capture disease at a single, often late, time point. To address this limitation, we used a clinically relevant model, the common marmoset (Callithrix jacchus) with experimental autoimmune encephalomyelitis (EAE), to study MS-like lesions. This model closely mimics MS lesion development and evolution, offering insights that are transferable to the clinical setting. Although structural magnetic resonance imaging (MRI) is noninvasive and effective for monitoring lesion changes, it lacks the specificity required to reveal the cellular and molecular diversity within lesions. Therefore, we integrated longitudinal MRI, histopathology, spatial transcriptomics, and single-nucleus RNA profiling to examine the signaling profiles involved in lesion development and resolution.

RESULTS
We identified five microenvironment (ME) groups—related to neural function, immune and glial responses, tissue destruction and repair, and regulatory networks at brain borders—that emerged during lesion evolution. Before visible demyelination, astrocytic and ependymal secretory signals marked perivascular and periventricular regions, which later became demyelination hotspots. We identified an MRI biomarker, the ratio of proton density–weighted signal to T₁ relaxation time, which was sensitive to the hypercellularity phase preceding myelin destruction. At lesion onset, we observed a global shift in cellular connectivity, particularly in extracellular matrix–mediated signaling. Early responses involved the proliferation and diversification of microglia and oligodendrocyte precursor cells (OPC). As lesions developed, EAE-associated glia were replaced by monocyte derivatives at the lesion center, with persistent lymphocytes seen in aged lesions. Concurrently with demyelination, reparative signaling modules appeared at the lesion edge as early as 10 days after lesion establishment. We also noted an overrepresentation of genes involved in the senescence-associated secretory phenotype (SASP) at the brain borders and the formation of concentric glial barriers at the lesion edge, prompting perturbation analysis to contextualize EAE-associated changes and identify potential therapeutics to protect tissue and enhance repair.

CONCLUSION
We identified a SERPINE1⁺ astrocytic subtype, acting as a secretory hub at the perivascular and periventricular zones, which underlies the onset of lesions in both marmoset EAE and MS. Our work offers a spatiotemporally resolved molecular map as a resource to benefit MS research and to guide identification of candidates for therapeutic intervention.

Dynamics of cells and microenvironments in perivascular and periventricular zones.
MS-like lesions form and expand near central veins and ventricles, enriched with SASP markers. Molecular and MRI biomarkers spatiotemporally define lesion stages. As lesions evolve, EAE-related (astrocyte_EAE, oligodendrocyte_EAE, OPC_EAE, microglia_EAE, ependyma_EAE, and VE_EAE), proliferative (leukocyte_Cyc, microglia_Cyc, and OPC_Cyc), and myelin-repairing (OPC_{differentiation}) cells dominate specific lesion zones, with SERPINE1⁺ astrocyte_EAE acting as a signaling hub at lesion edges during microenvironment transitions. Cyc, cycling; CSF, cerebrospinal fluid; DC, dendritic cell.

Abstract

Inferring cellular and molecular dynamics of multiple sclerosis (MS) lesions from postmortem tissue collected decades after onset is challenging. Using magnetic resonance image (MRI)–guided spatiotemporal RNA profiling in marmoset experimental autoimmune encephalitis (EAE), we mapped lesion dynamics and modeled molecular perturbations relevant to MS. Five distinct lesion microenvironments emerged, involving neuroglial responses, tissue destruction and repair, and brain border regulation. Before demyelination, MRI identified a high ratio of proton density–weighted signal to T₁ relaxation time, capturing early hypercellularity, and elevated astrocytic and ependymal senescence signals marked perivascular and periventricular areas that later became demyelination hotspots. As lesions expanded, concentric glial barriers formed, initially dominated by proliferating and diversifying microglia and oligodendrocyte precursors, later replaced by monocytes and lymphocytes. We highlight SERPINE1⁺ astrocytes as a signaling hub underlying lesion onset in both marmoset EAE and MS.