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Objective <p>White matter damage in Multiple Sclerosis (MS) exhibits significant heterogeneity. The cellular and molecular underpinnings of this heterogeneity are not fully understood. This study investigated cell-specific changes and spatial heterogeneity in MS white matter by integrating single-cell and spatial transcriptomics (ST) to guide potential clinical interventions.</p> Methods <p>Single-nucleus RNA sequencing (snRNA-seq) identified key cell types, regulons, and cellular functional heterogeneity using Gene Regulatory Network (GRN) analysis, cell communication, subpopulation classification, functional enrichment, and pseudotime analysis. ST explored functional heterogeneity and cell type distribution in MS white matter niches via correlation, enrichment analysis, and deconvolution.</p> Results <p>snRNA-seq analysis identified module M3, showing transcription factor dysregulation in MS white matter compared to controls. These genes were predominantly expressed in microglia and enriched in inflammation related signaling pathways; IKAROS Family Zinc Finger 1 (IKZF1) was identified as a candidate transcriptional regulator connected to these changes. Microglia exhibited heterogeneity, existing in dynamic regulation from homeostatic to pro-inflammatory phenotypes, the latter showing Disease-associated Microglia (DAM) characteristics. Spatial transcriptomic analysis revealed strong heterogeneity within MS white matter with distinct niche functions. The Lesion Rim (LR), a transition zone, correlated strongly with microglia and was highly enriched with DAM characteristics. The LR was identified as an inflammatory hotspot enriched for DAM and altered IKZF1 regulon activity, supporting snRNA-seq findings.</p> Conclusion <p>IKZF1 regulon inactivation in microglia coincides with altered white matter lesions in MS and dysregulated inflammatory pathways. Microglial heterogeneity in MS, including DAM phenotypes, extends beyond traditional polarization models. MS white matter displays significant spatial heterogeneity. Hindered remyelination in the LR may reflect inflammation from sustained microglial activation.</p>

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Microglial dysregulation and spatiotemporal dynamics of inflammation in multiple sclerosis white matter: an integrative transcriptomic analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • Keqiang Ma,
  • Qing Zhang,
  • Hong Du,
  • Huimin Peng,
  • Jiaxuan Kang,
  • Yisheng Cai,
  • Lijun Tan,
  • Xiangding Chen,
  • Can Bian,
  • Xiaochao Qu

摘要

Objective

White matter damage in Multiple Sclerosis (MS) exhibits significant heterogeneity. The cellular and molecular underpinnings of this heterogeneity are not fully understood. This study investigated cell-specific changes and spatial heterogeneity in MS white matter by integrating single-cell and spatial transcriptomics (ST) to guide potential clinical interventions.

Methods

Single-nucleus RNA sequencing (snRNA-seq) identified key cell types, regulons, and cellular functional heterogeneity using Gene Regulatory Network (GRN) analysis, cell communication, subpopulation classification, functional enrichment, and pseudotime analysis. ST explored functional heterogeneity and cell type distribution in MS white matter niches via correlation, enrichment analysis, and deconvolution.

Results

snRNA-seq analysis identified module M3, showing transcription factor dysregulation in MS white matter compared to controls. These genes were predominantly expressed in microglia and enriched in inflammation related signaling pathways; IKAROS Family Zinc Finger 1 (IKZF1) was identified as a candidate transcriptional regulator connected to these changes. Microglia exhibited heterogeneity, existing in dynamic regulation from homeostatic to pro-inflammatory phenotypes, the latter showing Disease-associated Microglia (DAM) characteristics. Spatial transcriptomic analysis revealed strong heterogeneity within MS white matter with distinct niche functions. The Lesion Rim (LR), a transition zone, correlated strongly with microglia and was highly enriched with DAM characteristics. The LR was identified as an inflammatory hotspot enriched for DAM and altered IKZF1 regulon activity, supporting snRNA-seq findings.

Conclusion

IKZF1 regulon inactivation in microglia coincides with altered white matter lesions in MS and dysregulated inflammatory pathways. Microglial heterogeneity in MS, including DAM phenotypes, extends beyond traditional polarization models. MS white matter displays significant spatial heterogeneity. Hindered remyelination in the LR may reflect inflammation from sustained microglial activation.