CRISPR-MI and scRNA-Seq Reveal TREM2's Function in Monocyte Infiltration and Macrophage Apoptosis During Abdominal Aortic Aneurysm Development

Haocheng Lu^{1

2}, Chao Xue^{2

3}, Yang Zhao², Jinjian Sun^{2

4}, Changzhi Zhao⁵, Xu Zhang², Guizhen Zhao², Yaozhong Liu², Hongyu Liu², Yongjie Deng², Ying Wang¹, Chi Zhang¹, Yingjie Liu¹, Linjun Zeng¹, Ying Yang¹, Bolun Li⁶, Shusi Ding⁷, Linkang Zhou⁸, Henry Kuang⁸, Zanxin Wang⁹, Wenhao Ju^{10

11}, Haihuan Lin¹, Jie Lin¹², Yanhong Guo², Lin Chang², Hongmei Zhao¹³, Jing Wang¹³, Jiandie Lin^{9

14}, Lemin Zheng^{8

15}, Y Eugene Chen², Jifeng Zhang²

Affiliations

¹ Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518033, P. R. China.
² Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Medical Center, Ann Arbor, MI, 48105, USA.
³ Department of Internal Medicine, Rochester General Hospital, Rochester, NY, 14621, USA.
⁴ Department of General &Vascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
⁵ Yazhouwan National Laboratory, Sanya, 572024, P. R. China.
⁶ Laboratory of Translational Genetics, Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
⁷ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100050, China.
⁸ Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
⁹ Department of Cardiovascular Surgery, The University of Hong Kong-Shenzhen Hospital, Guangdong, 518031, P. R. China.
¹⁰ Department of Structural Heart Disease, National Center for Cardiovascular Disease, China & Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100037, P. R. China.
¹¹ National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, 100037, P. R. China.
¹² Cardiology Department, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, P. R. China.
¹³ State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100050, P. R. China.
¹⁴ Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA.
¹⁵ The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing, 100191, P. R. China.

PMID: 41058009
DOI: 10.1002/advs.202412227

CRISPR-MI and scRNA-Seq Reveal TREM2's Function in Monocyte Infiltration and Macrophage Apoptosis During Abdominal Aortic Aneurysm Development

Haocheng Lu et al. Adv Sci (Weinh). 2025.

. 2025 Oct 7:e12227.

doi: 10.1002/advs.202412227. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518033, P. R. China.
² Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Medical Center, Ann Arbor, MI, 48105, USA.
³ Department of Internal Medicine, Rochester General Hospital, Rochester, NY, 14621, USA.
⁴ Department of General &Vascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
⁵ Yazhouwan National Laboratory, Sanya, 572024, P. R. China.
⁶ Laboratory of Translational Genetics, Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
⁷ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100050, China.
⁸ Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
⁹ Department of Cardiovascular Surgery, The University of Hong Kong-Shenzhen Hospital, Guangdong, 518031, P. R. China.
¹⁰ Department of Structural Heart Disease, National Center for Cardiovascular Disease, China & Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100037, P. R. China.
¹¹ National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, 100037, P. R. China.
¹² Cardiology Department, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, P. R. China.
¹³ State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100050, P. R. China.
¹⁴ Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA.
¹⁵ The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing, 100191, P. R. China.

PMID: 41058009
DOI: 10.1002/advs.202412227

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease without effective medication. The infiltration of monocytes into the aortic wall is critical for AAA development, but the genes and pathways regulating this process remain to be elucidated. A novel method is developed for in vivo genome-wide CRISPR/Cas9 screening of monocyte infiltration (CRISPR-MI). By combining CRISPR-MI with single-cell RNA sequencing (scRNA-Seq), this study finds that Triggering receptor expressed on myeloid cells 2 (Trem2) is a negative regulator of monocyte infiltration into the aortic wall in early AAA induction. Trem2 knockout (KO) increases the expression of adhesion molecules, chemotactic receptors, and cytokines in monocytes. Trem2 KO promotes monocyte adhesion and migration in vitro and increases monocyte infiltration into the aortic wall in vivo. However, Trem2 KO attenuates AAA development because of prominent macrophage death at the late stage. In conclusion, CRISPR-MI is a powerful tool for studying genes underlying monocyte infiltration in disease conditions in vivo. These findings reveal a dichotomous role of Trem2 in monocyte recruitment and macrophage survival during AAA.

Keywords: CRISPR screen; abdominal aortic aneurysm; apoptosis; inflammation; macrophage.

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CRISPR-MI and scRNA-Seq Reveal TREM2's Function in Monocyte Infiltration and Macrophage Apoptosis During Abdominal Aortic Aneurysm Development

Affiliations

CRISPR-MI and scRNA-Seq Reveal TREM2's Function in Monocyte Infiltration and Macrophage Apoptosis During Abdominal Aortic Aneurysm Development

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

Research Materials