Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques
Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions a...
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2024-12-01
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| author | Yunrui Lu Shuang Wu Shiyu Zhu Jian Shen Chang Liu Chaoyue Zhao Sheng’an Su Hong Ma Meixiang Xiang Yao Xie |
| author_facet | Yunrui Lu Shuang Wu Shiyu Zhu Jian Shen Chang Liu Chaoyue Zhao Sheng’an Su Hong Ma Meixiang Xiang Yao Xie |
| author_sort | Yunrui Lu |
| collection | DOAJ |
| description | Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high <i>NR1H3</i> expression; (iv) mature foamy macrophages prone to programmed cell death; and (v) synthetic subset. Trajectory analysis elucidated a bifurcated differentiation cell fate from pro-foam macrophages toward either the programmed death (iv) or synthetic (v) phenotype. The existence of these foamy macrophage subsets was validated by immunostaining. Moreover, these foamy macrophage subsets exhibited strong potential ligand–receptor interactions. Finally, we conducted Mendelian randomization analyses to identify a possible causal relationship between key regulatory genes along the programmed death pathway in foamy macrophages and atherosclerotic diseases. This study provides a high-resolution map of foam cell diversity and a set of potential key regulatory genes in atherosclerotic plaques, offering novel insights into the multifaceted pathophysiology underlying human atherosclerosis. |
| format | Article |
| id | doaj-art-e404025c14c747d49f835ccc56f5f813 |
| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Biomolecules |
| spelling | doaj-art-e404025c14c747d49f835ccc56f5f8132025-08-20T02:43:29ZengMDPI AGBiomolecules2218-273X2024-12-011412160610.3390/biom14121606Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic PlaquesYunrui Lu0Shuang Wu1Shiyu Zhu2Jian Shen3Chang Liu4Chaoyue Zhao5Sheng’an Su6Hong Ma7Meixiang Xiang8Yao Xie9State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaState Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaFoam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high <i>NR1H3</i> expression; (iv) mature foamy macrophages prone to programmed cell death; and (v) synthetic subset. Trajectory analysis elucidated a bifurcated differentiation cell fate from pro-foam macrophages toward either the programmed death (iv) or synthetic (v) phenotype. The existence of these foamy macrophage subsets was validated by immunostaining. Moreover, these foamy macrophage subsets exhibited strong potential ligand–receptor interactions. Finally, we conducted Mendelian randomization analyses to identify a possible causal relationship between key regulatory genes along the programmed death pathway in foamy macrophages and atherosclerotic diseases. This study provides a high-resolution map of foam cell diversity and a set of potential key regulatory genes in atherosclerotic plaques, offering novel insights into the multifaceted pathophysiology underlying human atherosclerosis.https://www.mdpi.com/2218-273X/14/12/1606atherosclerosisfoam cellsmacrophagesintegrated single-cell analysissingle-cell RNA sequencingMendelian randomization |
| spellingShingle | Yunrui Lu Shuang Wu Shiyu Zhu Jian Shen Chang Liu Chaoyue Zhao Sheng’an Su Hong Ma Meixiang Xiang Yao Xie Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques Biomolecules atherosclerosis foam cells macrophages integrated single-cell analysis single-cell RNA sequencing Mendelian randomization |
| title | Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques |
| title_full | Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques |
| title_fullStr | Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques |
| title_full_unstemmed | Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques |
| title_short | Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques |
| title_sort | integrated single cell analysis revealed novel subpopulations of foamy macrophages in human atherosclerotic plaques |
| topic | atherosclerosis foam cells macrophages integrated single-cell analysis single-cell RNA sequencing Mendelian randomization |
| url | https://www.mdpi.com/2218-273X/14/12/1606 |
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