Integrative transcriptomic analysis reveals distinct fibroblast subtypes that either promote pathological remodeling or orchestrate protective responses in intracranial aneurysms, offering novel therapeutic targets.
Intracranial aneurysm (IA) is characterized by vascular wall remodeling and extracellular matrix (ECM) dysregulation, leading to aneurysm formation and rupture. Fibroblasts, key regulators of ECM homeostasis, have been implicated in IA pathogenesis, but their functional heterogeneity and molecular mechanisms remain poorly defined. In this study, we integrated bulk and single-cell RNA sequencing datasets to investigate fibroblast subpopulations involved in IA progression. Using the GSE122897 dataset, we applied DESeq2 for differential expression analysis and WGCNA to construct gene co-expression networks. Hub genes were screened via MCODE and subjected to functional enrichment analysis. Their expression was subsequently validated in the GSE193533 mouse IA single-cell dataset, which included sham, formed, and ruptured aneurysm samples. Fibroblasts were reclustered to explore subtype heterogeneity and functional dynamics. Two upregulated gene co-expression modules were identified: an ECM remodeling module and a cilium/cytoskeleton organization module. Hub gene analysis revealed 14 key genes, including COL5A1, FSTL1, PRRX2, and ADAMTS2, which were enriched in pathways related to collagen metabolism, ECM organization, and epithelial apoptosis. Re-clustering of fibroblasts revealed two distinct subtypes: C1 and C2. The C1 subtype, characterized by high expression of FSTL1, likely contributes to a persistent inflammatory state and pathological remodeling, potentially exacerbating vessel wall weakening. In contrast, the C2 subtype, characterized by high expression of ADAMTS2 and PRRX2, appears to orchestrate a protective response. Clinically, our findings highlight the imbalance between these fibroblast states as a potential determinant of aneurysm stability. Strategies aimed at preserving the ADAMTS2-driven reparative capacity or inhibiting FSTL1-mediated remodeling may represent novel therapeutic avenues to prevent IA rupture.
Wei et al. (Mon,) studied this question.
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