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. 2023 Dec;43(12):2333-2347.
doi: 10.1161/ATVBAHA.123.319479. Epub 2023 Oct 26.

Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions

Kenji Kawai  1 , Atsushi Sakamoto  1 , Michal Mokry  2   3 , Saikat Kumar B Ghosh  1 , Rika Kawakami  1 , Weili Xu  1 , Liang Guo  1 , Daniela T Fuller  1 , Takamasa Tanaka  1 , Palak Shah  1 , Anne Cornelissen  1 , Yu Sato  1 , Masayuki Mori  1 , Takao Konishi  1 , Aimee E Vozenilek  1 , Roma Dhingra  1 , Renu Virmani  1 , Gerard Pasterkamp  2 , Aloke V Finn  1   4
Affiliations

Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions

Kenji Kawai et al. Arterioscler Thromb Vasc Biol. 2023 Dec.

Abstract

Background: Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model.

Methods: Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3'UTR of the X-linked BGN (biglycan) gene, a proteoglycan highly expressed by SMCs. BGN-specific BaseScope probes were designed to target the wild-type or deletion mRNA. Three different coronary artery plaque types (erosion, rupture, and adaptive intimal thickening) were selected from heterozygous females for the deletion BGN. Hybridization of target RNA-specific probes was used to visualize the spatial distribution of mutants. A clonality index was calculated from the percentage of each probe in each region of interest. Spatial transcriptomics were used to identify differentially expressed transcripts within clonal and nonclonal regions.

Results: Less than one-half of regions of interest in the intimal plaque were considered clonal with the mean percent regions of interest with clonality higher in the intimal plaque than in the media. This was consistent for all plaque types. The relationship of the dominant clone in the intimal plaque and media showed significant concordance. In comparison with the nonclonal lesions, the regions with SMC clonality had lower expression of genes encoding cell growth suppressors such as CD74, SERF-2 (small EDRK-rich factor 2), CTSB (cathepsin B), and HLA-DPA1 (major histocompatibility complex, class II, DP alpha 1), among others.

Conclusions: Our novel approach to examine clonality suggests atherosclerosis is primarily a disease of polyclonally and to a lesser extent clonally expanded SMCs and may have implications for the development of antiatherosclerotic therapies.

Keywords: atherosclerosis; biglycan; coronary artery disease; gene expression; pathology.

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Conflict of interest statement

Disclosures R. Virmani and A.V. Finn have received institutional research support from the National Institutes of Health (HL141425), Leducq Foundation Grant, 480 Biomedical, 4C Medical, 4Tech, Abbott, Accumedical, Amgen, Biosensors, Boston Scientific, Cardiac Implants, Celonova, Claret Medical, Concept Medical, Cook, CSI, DuNing, Inc, Edwards LifeSciences, Emboline, Endotronix, Envision Scientific, Lutonix/Bard, Gateway, Lifetech, Limflo, MedAlliance, Medtronic, Mercator, Merill, Microport Medical, Microvention, Mitraalign, Mitra Assist, NAMSA, Nanova, Neovasc, NIPRO, Novogate, Occulotech, OrbusNeich Medical, Phenox, Profusa, Protembis, Qool, Recor, Senseonics, Shockwave, Sinomed, Spectranetics, Surmodics, Symic, Vesper, W.L. Gore, and Xeltis. A.V. Finn has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, and Terumo Corporation and is a consultant at Amgen, Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Lutonix Bard, and Sinomed. R. Virmani has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Lutonix Bard, Medtronic, OrbusNeich Medical, Celonova, SINO Medical Technology, ReCor, Terumo Corporation, W.L. Gore, and Spectranetics and is a consultant at Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Edwards Lifesciences, Lutonix Bard, Medtronic, OrbusNeich Medical, ReCor, Sinomededical Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore, and Xeltis. The other authors report no conflicts.

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