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Background <p>Abdominal aortic aneurysm (AAA) rupture remains the leading cause of AAA-related mortality, while current clinical management relies primarily on aneurysm diameter, which inadequately predicts rupture risk. Increasing evidence suggests that stromal cell heterogeneity critically shapes vascular remodeling; however, the specific fibroblast states associated with AAA rupture predisposition remain poorly defined.</p> Methods <p>We integrated cross-species single-cell RNA-sequencing datasets spanning the full spectrum of AAA progression to systematically characterize fibroblast heterogeneity and state transitions. Pseudotime trajectory analysis, transcriptional regulatory network inference, and ligand–receptor interaction modeling were applied to delineate fibroblast-associated microenvironmental programs. Based on these findings, a fibroblast-derived molecular signature was constructed and validated in an independent human AAA cohort.</p> Results <p>Single-cell analysis revealed a progressive transition from homeostatic IGFBP6<sup>+</sup> fibroblasts to a disease-associated COL10A1<sup>+</sup> fibroblast state during AAA progression. COL10A1<sup>+</sup> fibroblasts were selectively enriched in rupture-prone lesions and exhibited transcriptional programs linked to extracellular matrix remodeling and osteogenic-like activation. Intercellular communication analysis indicated that COL10A1<sup>+</sup> fibroblasts were predicted to engage macrophage populations through coordinated ligand–receptor signaling pathways, including MDK, CSF1, and CXCL12, collectively delineating a rupture-associated vascular microenvironment. Translationally, leveraging this fibroblast state enabled the development of a minimal two-gene risk score (COL10A1–IGFBP6), which stratified AAA patients by molecular rupture risk independently of aneurysm diameter in the validation cohort.</p> Conclusions <p>This study identifies a COL10A1<sup>+</sup> fibroblast–associated transcriptional state that defines a rupture-prone vascular microenvironment in abdominal aortic aneurysm. The derived COL10A1–IGFBP6 signature establishes a biologically informed framework for molecular risk stratification, complementing anatomical size–based assessment and providing a foundation for future development of mechanism-guided strategies to refine AAA risk evaluation.</p>

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COL10A1+ fibroblasts define rupture-prone abdominal aortic aneurysms and enable molecular risk stratification

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Huawei Zhuo,
  • Chengxin Ou,
  • Meng Duan,
  • Jiwu Yang,
  • Dan Liu

摘要

Background

Abdominal aortic aneurysm (AAA) rupture remains the leading cause of AAA-related mortality, while current clinical management relies primarily on aneurysm diameter, which inadequately predicts rupture risk. Increasing evidence suggests that stromal cell heterogeneity critically shapes vascular remodeling; however, the specific fibroblast states associated with AAA rupture predisposition remain poorly defined.

Methods

We integrated cross-species single-cell RNA-sequencing datasets spanning the full spectrum of AAA progression to systematically characterize fibroblast heterogeneity and state transitions. Pseudotime trajectory analysis, transcriptional regulatory network inference, and ligand–receptor interaction modeling were applied to delineate fibroblast-associated microenvironmental programs. Based on these findings, a fibroblast-derived molecular signature was constructed and validated in an independent human AAA cohort.

Results

Single-cell analysis revealed a progressive transition from homeostatic IGFBP6+ fibroblasts to a disease-associated COL10A1+ fibroblast state during AAA progression. COL10A1+ fibroblasts were selectively enriched in rupture-prone lesions and exhibited transcriptional programs linked to extracellular matrix remodeling and osteogenic-like activation. Intercellular communication analysis indicated that COL10A1+ fibroblasts were predicted to engage macrophage populations through coordinated ligand–receptor signaling pathways, including MDK, CSF1, and CXCL12, collectively delineating a rupture-associated vascular microenvironment. Translationally, leveraging this fibroblast state enabled the development of a minimal two-gene risk score (COL10A1–IGFBP6), which stratified AAA patients by molecular rupture risk independently of aneurysm diameter in the validation cohort.

Conclusions

This study identifies a COL10A1+ fibroblast–associated transcriptional state that defines a rupture-prone vascular microenvironment in abdominal aortic aneurysm. The derived COL10A1–IGFBP6 signature establishes a biologically informed framework for molecular risk stratification, complementing anatomical size–based assessment and providing a foundation for future development of mechanism-guided strategies to refine AAA risk evaluation.