Immune interaction signatures in adipose tissue fibroblasts in obesity-associated atherosclerosis

2025 · doi:10.1101/2025.09.02.673686
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The study investigated how obesity alters immune-related cellular interactions in perivascular and other adipose tissues during atherosclerosis progression, using Ldlr-/-Apob100/100 male mice fed high-fat versus control diets. Using 5’ single-cell RNA sequencing with antibody-based CITE-seq and CD45+ enrichment in aorta, the authors profiled ~46,000 cells across aorta, perivascular and epididymal adipose, and spleen, and assessed cell states, gene enrichment, regulon activity, and inferred interactions; key results were validated in mice with immunohistochemistry and multiplexed immunofluorescence and examined in human aorta/carotid arteries with spatial transcriptomics. They found obesity-associated transcriptional programs in adipose-derived fibroblast subsets, including a reduction in Pi16+ progenitor fibroblasts alongside pronounced PVAT remodeling with spatially patterned gene expression in human arteries. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Atherosclerosis involves changes in the vascular wall and surrounding perivascular adipose tissue, yet the cellular contributors to disease progression remain incompletely understood. Obesity exacerbates atherogenesis, but the cell types driving this aggravation are unclear. We aimed to define the key cell populations across tissues in a highly atherogenic mouse model under obese and normal-weight conditions and to identify obesity-associated cellular changes. We employed 5’ single-cell RNA sequencing combined with antibody staining in Ldlr -/- Apob 100/100 male mice fed either a high-fat or control diet. Aorta, perivascular and epididymal adipose tissues, and spleen were analyzed, with CD45⁺ enrichment of aortic samples and CITE-seq using a 138-antibody panel. Key findings were validated in mice by immunohistochemistry and multiplexed immunofluorescence and explored in human aorta and carotid arteries using spatial transcriptomics. Analysis of ∼46,000 cells enabled characterization of cell states, gene enrichment, regulon activity, and inferred interactions. Adipose-derived fibroblast subsets displayed immune-associated transcriptional programs in obesity. Pi16⁺ progenitor fibroblasts were reduced alongside marked PVAT remodeling, and the top mouse differentially expressed genes exhibited clear spatial patterning in human arteries.
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Abstract Atherosclerosis involves changes in the vascular wall and surrounding perivascular adipose tissue, yet the cellular contributors to disease progression remain incompletely understood. Obesity exacerbates atherogenesis, but the cell types driving this aggravation are unclear. We aimed to define the key cell populations across tissues in a highly atherogenic mouse model under obese and normal-weight conditions and to identify obesity-associated cellular changes. We employed 5’ single-cell RNA sequencing combined with antibody staining in Ldlr-/-Apob100/100 male mice fed either a high-fat or control diet. Aorta, perivascular and epididymal adipose tissues, and spleen were analyzed, with CD45⁺ enrichment of aortic samples and CITE-seq using a 138-antibody panel. Key findings were validated in mice by immunohistochemistry and multiplexed immunofluorescence and explored in human aorta and carotid arteries using spatial transcriptomics. Analysis of ∼46,000 cells enabled characterization of cell states, gene enrichment, regulon activity, and inferred interactions. Adipose-derived fibroblast subsets displayed immune-associated transcriptional programs in obesity. Pi16⁺ progenitor fibroblasts were reduced alongside marked PVAT remodeling, and the top mouse differentially expressed genes exhibited clear spatial patterning in human arteries. Competing Interest Statement The authors have declared no competing interest. Footnotes aydinbol{at}uef.fi, mmpiip{at}utu.fi, ivana.mikocziova{at}utu.fi, mira.valkonen{at}tuni.fi, jimmy.c.fagersund{at}utu.fi, haheha{at}utu.fi, antsaras{at}utu.fi, anhernandez{at}recerca.clinic.cat, palsen{at}utu.fi, tiit.ord{at}uef.fi, aroivan{at}utu.fi, pekka.ruusuvuori{at}utu.fi, merja.heinaniemi{at}uef.fi, minna.kaikkonen{at}uef.fi The manuscript has been revised according to reviewer comments.

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