Muredach Reilly | Tumor-like behavior of stromal cells in atherosclerosis

Muredach Reilly, Columbia University Irving Medical Center, United States Title: Tumor-like behavior of stromal cells in atherosclerosis Abstract: Recent work by the Reilly group on how atherosclerosis is a tumor-like disease of smooth muscle cells (SMC) will be reviewed and implications considered. Two novel findings will be presented. First, to define the phenotypic diversity and regulation of SMCs including SMC-foam cells in atherosclerosis, we performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and bulk RNA sequencing in SMC lineage-tracing Ldlr-/- mice. Single-cell multi-omics revealed cellular heterogeneity within atherosclerotic plaques, including rare SMC-derived macrophage-like cells, confirmed by immunohistology. We also identified that SMC-derived foam cells comprised approximately 70% of all foam cells in lesions. These cells exhibited activation of gene programs for lipid metabolism, proliferation, and tumor-like features. The transcription factor Bhlhe40 emerged as a master regulator of this phenotypic transition. Knockdown of Bhlhe40 suppressed SMC phenotypic switching and foam cell characteristics, underscoring its potential to drive SMC modulation. Second, we used SMC lineage tracing with scRNA-seq, spatial transcriptomics, and histological analyses in Myh11 CreERT2; Ldlr–/–; Rosa26 ZsGreen1 mice to define which cell types drive plaque remodeling during 20 weeks of LDL-C lowering. LDL-C reduction triggered early resolution of inflammation, a buildup of collagen and thickening of the fibrous cap, without lesion area regression. scRNA-seq showed that this transition coincided with a selective expansion of fibroblast subpopulations, most prominently Pi16⁺CD26⁺ and Mmp3⁺Fmod⁺ fibroblasts. Both fibroblast subsets engaged robust collagen biosynthetic programs but differed in activation dynamics and spatial context. Master regulator analysis highlighted Klf3 as a pivotal transcription factor maintaining the Pi16⁺CD26⁺ phenotype. Computational modeling predicted that loss of Klf3 would shift fibroblasts toward an Mmp3⁺Fmod⁺ state. Concordantly, Klf3 silencing in mouse and human aortic fibroblasts reduced collagen expression, proliferation, and migration. scRNA-seq and spatial analyses of human carotid atherosclerosis revealed conserved fibroblast diversity and KLF3 enrichment within fibrous cap. This work suggests a key role for specific fibroblast subtypes in plaque remodeling during LDL-C lowering. #CardioWorldCongress2026 #WCAC2026 #Cardiology2026 #Cardiology #CardiovascularResearch #Cardiologist #HeartDisease #HeartHealth #CardiologyConference #MedicalConference #Healthcare #CardiologyEducation #PreventiveCardiology #Rome #HybridConference #CardioWorldCongress