A1 Refereed original research article in a scientific journal
Single-cell to pre-clinical evaluation of Trem2, Folr2, and Slc7a7 as macrophage-associated biomarkers for atherosclerosis
Authors: Örd, Tiit; Palani, Senthil; Giroud Gerbetant, Judith; Bodoy, Susanna; Lönnberg, Tapio; Niskanen, Henri; Ravindran, Aarthi; Holappa, Lari; Chemaly, Melody; Taipale, Mari; Õunap, Kadri; Haikonen, Retu; Talukdar, Husain; Sukhavasi, Katyayani; Liljenbäck, Heidi; Virta, Jenni; Ruotsalainen, Anna-Kaisa; Pierrot-Blanchet, Clara; Miner, Maxwell W. G.; Moisio, Olli; Rajala, Noora; Li, Xiang-Guo; Low, Philip S.; Saraste, Antti; Heinäniemi, Merja; Ylä-Herttuala, Seppo; Björkegren, Johan L. M.; Hedin, Ulf; Matic, Ljubica; Yvan-Charvet, Laurent; Palacin, Manuel; Roivainen, Anne; Kaikkonen, Minna U.
Publisher: Oxford University Press (OUP)
Publication year: 2025
Journal:Cardiovascular Research
Article number: cvaf210
ISSN: 0008-6363
eISSN: 1755-3245
DOI: https://doi.org/10.1093/cvr/cvaf210
Web address : https://doi.org/10.1093/cvr/cvaf210
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/505284588
Aims
Atherosclerosis is a major global health challenge, with limited diagnostic and therapeutic options. Macrophages drive disease progression, but their tissue-specific phenotypes and functions remain poorly defined. This study aims to elucidate macrophage-driven mechanisms by characterizing their functional diversity across key metabolic and vascular tissues.
Methods and Results
We used single-cell RNA sequencing (scRNA-seq) and Translating Ribosome Affinity Purification sequencing (TRAP-seq) to profile macrophage-specific gene programs in a mouse model of atherosclerosis across the aorta, adipose tissue, and liver. Our data highlights tissue-specific macrophage gene programs and identifies markers that are shared across mouse and human plaques. First, we identified soluble Trem2 as a potential circulating biomarker for differentiating between asymptomatic and symptomatic individuals. Secondly, we leveraged the pronounced expression of Folr2 and Slc7a7 to explore the potential of folate and glutamine as PET tracers for disease burden assessment through in vivo positron emission tomography (PET) imaging. Finally, we show that knockout of Slc7a7 inhibits acetylated low-density lipoprotein (AcLDL) uptake and dampens the gene signature linked to lipid-associated macrophages. This suggests that glutamine signaling may play a critical role in foam cell formation, a key event in atherosclerosis.
Conclusions
Our findings provide novel insights into macrophage-specific gene programs during atherosclerosis progression and identify a set of promising biomarkers that can serve as a resource for future studies. These findings could significantly contribute to improving the diagnosis, monitoring, and treatment of atherosclerosis.
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Funding information in the publication:
This study was funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant No. 802825 to M.U.K), Research Council of Finland (Grants Nos. 314556 and 335975 to A.Ro, 333021 and 335973 to M.U.K, 352968 to T.Ö and M.T, 335964 to M.H, 350049 to A-K.R), Finnish Foundation for Cardiovascular Research (A-K.R, A.Ro, M.U.K), Sigrid Juselius Foundation (A.S, A.Ro and M.U.K), Spanish Ministry of Science and Innovation (PID2021-122802OB-I00 to M.P and S.B), Jane and Aatos Erkko Foundation (to A.R.), Finnish Cultural Foundation (to S.P.), Turku University Foundation (to S.P.), Orion Research Foundation (to A-K.R.), the ANR (grants 20- CE14-CHIC and 24-CE14-Glutacare to L.Y.C), and the University of Eastern Finland Doctoral Program of Molecular Medicine. A.Ra was supported by the Genomics and Mechanisms in Translational Medicine (GenomMed) Doctoral Programme, cofunded by the Horizon 2020 Framework Programme of the European Union, Marie Skłodowska-Curie grant agreement no. 740264.This research was supported by InFLAMES Flagship Programme of the Research Council of Finland (decision number: 337530). J.L.M.B. acknowledges support from the Swedish Research Council (2018-02529 and 2022-00734), the Swedish Heart Lung Foundation (2017-0265 and 2020-0207), the Leducq Foundation AtheroGen (22CVD04) and PlaqOmics (18CVD02) consortia; the National Institute of Health-National Heart Lung Blood Institute (NIH/NHLBI, R01HL164577; R01HL148167; R01HL148239, R01HL166428, and R01HL168174), American Heart Association Transformational Project Award 19TPA34910021, and from the CMD AMP fNIH program. L.M. is the recipient of fellowships and awards from the Swedish Research Council [VR, 2023-02724, 2019-02027], Karolinska Institute Consolidator program, Swedish Heart-Lung Foundation [HLF, 20240094, 20230357, 20210466, 20200621, 20200520, 20180244, 20180247, 201602877] and Swedish Society for Medical Research [SSMF, P13-0171]. L.M. also acknowledges funding from Mats Kleberg’s, Sven and Ebba-Christina Hagberg’s, Tore Nilsson’s, Magnus Bergvall’s and Karolinska Institute research (KI Fonder) and doctoral education (KID) foundations. The work of L.M. was also funded by a research grant from the European Union’s Horizon Europe program under grant agreement No 101136962 (NextGen). Project funding was also obtained by U.H. from the Swedish Heart-Lung Foundation (20180036, 20170584), the Swedish Research Council (2017-01070, 2019-02027), and King Gustav Vth and Queen Victoria’s Foundation.
