Integrated single-cell multi-omics analysis identifies fibroblast-like smooth muscle cells as a key driving...

Aortic aneurysm (AA) is a life-threatening vascular disorder characterized by smooth muscle cell (SMC) phenotypic switching. However, SMC heterogeneity and the regulatory mechanisms underlying this transition remain incompletely understood.

We integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) data from healthy and AA-affected human aortic tissues to characterize SMC heterogeneity. Computational analyses, trajectory inference, and pathway enrichment analyses were performed. Key findings were validated by immunofluorescence staining, animal models, and in vitro experiments using human aortic smooth muscle cells (HASMCs).

Sixteen major cell types and eight distinct SMC subpopulations were identified. Fibroblast-like SMCs (Fib-like SMCs) were strongly associated with AA progression, as supported by computational analyses and immunofluorescence staining. Trajectory analysis suggested that Fib-like SMCs exhibit high differentiation potential and occupy a putative progenitor-like position, giving rise to other SMC subtypes. Transcriptomic and metabolic analyses revealed enhanced glycolytic reprogramming, suggesting increased lactate production and lactylation-associated activity. KAT5 was identified as a central regulator mediating histone lactylation and driving Fib-like SMC phenotypic modulation. In vitro experiments demonstrated that KAT5 maintains elevated cellular stemness in human aortic SMCs by activating the Wnt signaling pathway, upregulating KLF4 expression, and inducing H4K12 lactylation.

Fib-like SMCs represent a key progenitor-like population driving SMC phenotypic switching during AA progression through a KAT5-mediated metabolic-epigenetic regulatory axis, providing new insights into arterial wall remodeling in AA.