Single-nucleus transcriptomic profiling reveals temporal dynamics of neuroinflammation and myelin repair after intracerebral haemorrhage

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-09-28 DOI:10.1002/ctm2.70486

Zhan Chen, Qinglin Wang, Rong Xiang, Ruoqi Ding, Jin Tao, Qinfeng Peng, Shaoshuai Wang, Nannan Cheng, Mengke Zhao, Jiaxin Li, Qidi Xue, Chuanyu Liu, Xuemei Chen, Longqi Liu, Junmin Wang, Jian Wang, Mingyue Wang

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引用次数: 0

Abstract

Background

Intracerebral haemorrhage (ICH) progresses rapidly with complex pathology and limited treatment options, making it a severe subtype of stroke. The extravasation of blood into the brain parenchyma triggers a cascade of inflammatory responses, contributing to secondary injury. Single-nucleus RNA sequencing (snRNA-seq) data have enabled more profound insights into the cellular heterogeneity and dynamic interactions within the haemorrhagic brain. Immune cells play a crucial role in shaping neuroinflammation. However, the lack of comprehensive longitudinal studies limits our understanding of the temporal evolution of these inflammatory processes, posing a challenge to the development of targeted therapeutic strategies.

Methods

We used snRNA-seq in collagenase-induced ICH mouse models at Days 1, 3, 7, 14 and 28 post-injury, alongside naive controls, to profile the dynamics of gene expression over time.

Results

We obtained 281 577 high-quality transcriptional profiles representing 21 distinct cell types. Co-expression network analysis revealed a prominent ‘inflammation module’ that remained active throughout ICH. Integrative single-cell transcriptomic and immunofluorescence staining suggested that the various Mif-expressing cells may contribute to local inflammation, potentially engaging macrophages via receptor–ligand pairs such as Cd44 and Cd74. Over time, microglia appeared to serve as key recipients of pro-inflammatory signals increasingly. During the resolution phase, oligodendrocytes exhibited transcriptional signatures consistent with enhanced maturation and remyelination, which T cell-mediated interactions may have facilitated.

Conclusions

These findings offer a systems-level perspective on cell-type–specific responses and immune-mediated interactions during ICH progression and resolution.

Key points

Establish intracerebral haemorrhage (ICH) mouse models at various time points (Days 1, 3, 7, 14, 28) and construct a high-quality single-nucleus RNA sequencing (snRNA-seq) atlas.
Computational analyses suggest that macrophage recruitment in the early stage of ICH potentially involves migration inhibitory factor (MIF) signalling pathways.
T cells may interact with myelin-forming oligodendrocytes during the resolution phase, potentially contributing to remyelination after ICH.

Abstract Image

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单核转录组分析揭示脑出血后神经炎症和髓鞘修复的时间动态。

背景：脑出血（ICH）进展迅速，病理复杂，治疗方案有限，是脑卒中的一种严重亚型。血液外渗到脑实质引发一连串的炎症反应，导致继发性损伤。单核RNA测序（snRNA-seq）数据使我们能够更深入地了解出血性脑内的细胞异质性和动态相互作用。免疫细胞在形成神经炎症中起着至关重要的作用。然而，缺乏全面的纵向研究限制了我们对这些炎症过程的时间演变的理解，对靶向治疗策略的发展提出了挑战。方法：我们在损伤后第1、3、7、14和28天使用snRNA-seq对胶原酶诱导的脑出血小鼠模型进行分析，以分析基因表达随时间的变化。结果：我们获得了281577个高质量的转录谱，代表21种不同的细胞类型。共表达网络分析揭示了一个突出的“炎症模块”在整个ICH中保持活跃。综合单细胞转录组学和免疫荧光染色表明，各种表达mif的细胞可能有助于局部炎症，可能通过Cd44和Cd74等受体配体对参与巨噬细胞。随着时间的推移，小胶质细胞似乎越来越多地成为促炎信号的关键接受者。在分化阶段，少突胶质细胞表现出与增强的成熟和髓鞘再生一致的转录特征，这可能是T细胞介导的相互作用促进的。结论：这些发现为脑出血进展和消退过程中细胞类型特异性反应和免疫介导的相互作用提供了系统水平的视角。重点：在不同时间点（第1、3、7、14、28天）建立脑出血（ICH）小鼠模型，构建高质量的单核RNA测序（snRNA-seq）图谱。计算分析表明，巨噬细胞募集在脑出血早期可能涉及迁移抑制因子（MIF）信号通路。在分解期，T细胞可能与髓磷脂形成的少突胶质细胞相互作用，可能有助于脑出血后的髓鞘再生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.