Examining the Development of Chronic Thromboembolic Pulmonary Hypertension at the Single-Cell Level

Author:

Miao Ran123,Dong Xingbei4,Gong Juanni23,Li Yidan5,Guo Xiaojuan6,Wang Jianfeng7,Huang Qiang7ORCID,Wang Ying8,Li Jifeng23ORCID,Yang Suqiao23ORCID,Kuang Tuguang23,Liu Min9,Wan Jun1011,Zhai Zhenguo1011ORCID,Zhong Jiuchang12,Yang Yuanhua23ORCID

Affiliation:

1. Medical Research Center (R.M.), Beijing Chao-Yang Hospital, Capital Medical University, China.

2. Department of Respiratory and Critical Care Medicine (R.M., J.G., J.L., S.Y., T.K., Y.Y.), Beijing Chao-Yang Hospital, Capital Medical University, China.

3. Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Institute of Respiratory Medicine, Beijing, China (R.M., J.G., J.L., S.Y., T.K., Y.Y.).

4. Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China (X.D.).

5. Department of Echocardiography (Y.L.), Beijing Chao-Yang Hospital, Capital Medical University, China.

6. Department of Radiology (X.G.), Beijing Chao-Yang Hospital, Capital Medical University, China.

7. Department of Interventional Radiology (J. Wang, Q.H.), Beijing Chao-Yang Hospital, Capital Medical University, China.

8. Department of Pathology (Y.W.), Beijing Chao-Yang Hospital, Capital Medical University, China.

9. Department of Radiology (M.L.), China-Japan Friendship Hospital, Beijing, China.

10. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine (J. Wan, Z.Z.), China-Japan Friendship Hospital, Beijing, China.

11. National Clinical Research Center for Respiratory Diseases, Beijing, China (J. Wan, Z.Z.).

12. Heart Center and Beijing Key Laboratory of Hypertension (J.Z.), Beijing Chao-Yang Hospital, Capital Medical University, China.

Abstract

Background: The mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is known to be multifactorial but remains incompletely understood. Methods: In this study, single-cell RNA sequencing, which facilitates the identification of molecular profiles of samples on an individual cell level, was applied to investigate individual cell types in pulmonary endarterectomized tissues from 5 patients with CTEPH. The order of single-cell types was then traced along the developmental trajectory of CTEPH by trajectory inference analysis, and intercellular communication was characterized by analysis of ligand-receptor pairs between cell types. Finally, comprehensive bioinformatics tools were used to analyze possible functions of branch-specific cell types and the underlying mechanisms. Results: Eleven cell types were identified, with immune-related cell types (T cells, natural killer cells, macrophages, and mast cells) distributed in the left (early) branch of the pseudotime tree, cancer stem cells, and CRISPLD2+ cells as intermediate cell types, and classic disease-related cell types (fibroblasts, smooth muscle cells, myofibroblasts, and endothelial cells) in the right (later) branch. Ligand-receptor interactions revealed close communication between macrophages and disease-related cell types as well as between smooth muscle cells and fibroblasts or endothelial cells. Moreover, the ligands and receptors were significantly enriched in key pathways such as the PI3K/Akt signaling pathway. Furthermore, highly expressed genes specific to the undefined cell type were significantly enriched in important functions associated with regulation of endoplasmic reticulum stress. Conclusions: This single-cell RNA sequencing analysis revealed the order of single cells along a developmental trajectory in CTEPH as well as close communication between different cell types in CTEPH pathogenesis.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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