Spatial Transcriptomics Reveals CXCL12 + Fibroblasts as Central Immune Organizers through CXCR4 Signaling in
Dina Levy-Lambert1, Joel L Ramirez2, Saba Shaikh3
1Department of Surgery, University of California San Francisco, San Francisco, CA, United States.
Background:
Abdominal aortic aneurysm (AAA) is characterized by sterile inflammation, immune cell infiltration, and stromal remodeling that progressively weaken the aortic wall, leading to life-threatening aortic rupture. The molecular mechanisms and spatial organization of immune-stromal interactions in human tissue are poorly understood, limiting the potential to develop effective pharmacological therapy for AAA.
Methods:
In this observational cross-sectional study, formalin-fixed, paraffin-embedded tissues from 11 AAA patients and 12 controls were analyzed by Xenium spatial transcriptomics. Cellular states and localization within tissue architecture were mapped to identify cellular neighborhoods and infer cell-cell communication.
Results:
We generated a high-resolution spatial transcriptomics atlas of 581,664 cells in 26 clusters. AAAs showed a significant loss of contractile smooth muscle cells, expansion of pro-angiogenic endothelial subsets, and broad infiltration of immune cells. These inflammatory changes were accompanied by expansion of activated, universal, and CXCL12 + adventitial fibroblasts. Spatial transcriptomic analysis revealed fibroblast-immune colocalization and adventitial tertiary lymphoid organs. Inferred signaling pathway analysis identified increased interactions between CXCL12 + fibroblasts and CXCR4 + T and B cells in the adventitia of AAAs. Fibroblasts that expressed CXCL12 had significantly more immune cell neighbors than fibroblasts that did not, suggesting that they serve as stromal hubs for adaptive immune clustering. Genome-wide association analysis linked AAA heritability to fibroblasts, modulated smooth muscle cells, and foamy macrophages.
Conclusion:
Our novel high-resolution spatial transcriptomic atlas of human AAAs revealed coordinated pathogenic reprogramming of stromal and immune cells, defined by smooth muscle cell depletion, fibroblast activation, endothelial remodeling, and disproportionate expansion of immune cells. Through CXCR4 signaling, CXCL12 + fibroblasts serve as central organizers of immune niches, suggesting stromal-immune crosstalk as a therapeutic target in AAA.
