4D marmoset brain map reveals MRI and molecular signatures for onset of multiple sclerosis–like lesions

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-02-28

Jing-Ping Lin, Alexis Brake, Maxime Donadieu, Amanda Lee, Ginger Smith, Kevin Hu, Govind Nair, Riki Kawaguchi, Pascal Sati, Daniel H. Geschwind, Steven Jacobson, Dorothy P. Schafer, Daniel S. Reich

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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.

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从发病数十年后收集的尸检组织中推断多发性硬化症（MS）病变的细胞和分子动态具有挑战性。利用磁共振成像（MRI）引导的狨猴实验性自身免疫性脑炎（EAE）时空 RNA 分析，我们绘制了病变动态图，并模拟了与多发性硬化症相关的分子扰动。我们发现了五种不同的病变微环境，涉及神经胶质细胞反应、组织破坏和修复以及脑边界调控。在脱髓鞘之前，核磁共振成像发现质子密度加权信号与T1弛豫时间的比率很高，捕捉到了早期的高细胞性，而星形胶质细胞和上皮细胞衰老信号的升高标志着血管周围和脑室周围区域，这些区域后来成为脱髓鞘热点。随着病变的扩大，形成了同心胶质屏障，最初以增殖和多样化的小胶质细胞和少突胶质细胞前体为主，后来被单核细胞和淋巴细胞所取代。我们强调 SERPINE1+ 星形胶质细胞是狨猴 EAE 和多发性硬化症病变发生的信号枢纽。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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