Single-Cell Transcriptome Profiles Reveal Fibrocytes as Potential Targets of Cell Therapies for Abdominal Aortic Aneurysm.

Bolun Li,Zhiwei Li,Ran Gao,Weipeng Ge,Peiran Yang,Huiyuan Hu,Xiaomin Song,Hongmei Zhao,Zhifa Han,Tianfei Fan,Wenjun Guo,Yangfeng Hou,Jing Wang

doi:10.3389/fcvm.2021.753711

Abstract

Abdominal aortic aneurysm (AAA) is potentially life-threatening in aging population due to the risk of aortic rupture and a lack of optimal treatment. The roles of different vascular and immune cells in AAA formation and pathogenesis remain to be future characterized. Single-cell RNA sequencing was performed on an angiotensin (Ang) II-induced mouse model of AAA. Macrophages, B cells, T cells, fibroblasts, smooth muscle cells and endothelial cells were identified through bioinformatic analyses. The discovery of multiple subtypes of macrophages, such as the re-polarization of Trem2+Acp5+ osteoclast-like and M2-like macrophages toward the M1 type macrophages, indicates the heterogenous nature of macrophages during AAA development. More interestingly, we defined CD45+COL1+ fibrocytes, which was further validated by flow cytometry and immunostaining in mouse and human AAA tissues. We then reconstituted these fibrocytes into mice with Ang II-induced AAA and found the recruitment of these fibrocytes in mouse AAA. More importantly, the fibrocyte treatment exhibited a protective effect against AAA development, perhaps through modulating extracellular matrix production and thus enhancing aortic stability. Our study reveals the heterogeneity of macrophages and the involvement of a novel cell type, fibrocyte, in AAA. Fibrocyte may represent a potential cell therapy target for AAA.

Highlights

Abdominal aortic aneurysm (AAA) is an aging-related vascular disease
To explore the cell types involved in AAA, apolipoprotein E–deficient (ApoE−/−) male mice were implanted with Ang II osmotic pump for 4 weeks to induce AAA or underwent sham surgery, and the tissues were collected for scRNAseq (Figure 1A)
We focused on the heterogeneity of macrophage subtypes, and discovered the repolarization of M2like and Trem2+ osteoclast-like macrophages toward M1-like macrophages, highlighting a critical role of this process in AAA pathogenesis

Summary

Introduction

Abdominal aortic aneurysm (AAA) is an aging-related vascular disease. During the progression of AAA, the aneurysm slowly expands and acutely causes vessel rupture without any symptom and warning in advance, resulting in high mortality. For patients with ruptured AAAs, endovascular repair or open repair are the main clinical remedies. Even undergoing intervention for repair, the in-hospital mortality is still as high as 53.1% [1]. New therapies, such cell or stem cell therapies, have been proposed but have encountered difficulties in their development. It is necessary to investigate the mechanism of AAA formation and identify the novel biomarkers or therapies to diagnose and treat AAA patients

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Results

Conclusion