基于单细胞测序技术解析冠状动脉粥样硬化患者平滑肌细胞的细胞间通信及关键基因

doi:10.3969/j.issn.1674-8115.2024.02.003

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (2): 169-182.doi: 10.3969/j.issn.1674-8115.2024.02.003

• 论著 · 基础研究 • 上一篇

基于单细胞测序技术解析冠状动脉粥样硬化患者平滑肌细胞的细胞间通信及关键基因

司春婴¹^,²(), 王建茹², 李晓辉²(), 王永霞¹^,², 关怀敏²

^1.河南中医药大学第一临床医学院（中西医结合学院），郑州 450003
^2.河南中医药大学第一附属医院心脏中心/国家区域（中医）心血管诊疗中心，郑州 450003

收稿日期:2023-05-19 接受日期:2023-12-11 出版日期:2024-02-28 发布日期:2024-03-25
通讯作者: 李晓辉 E-mail:chunyingsi1987@163.com;478103511@qq.com
作者简介:司春婴（1987—），男，讲师，主治医师，硕士；电子信箱：chunyingsi1987@163.com。
基金资助:
河南省自然科学基金青年基金项目(232300420273);河南省医学科技攻关计划联合共建项目(LHGJ20230690);国家自然科学基金青年基金项目(82205021);河南省科技攻关项目(212102311083);河南中医药大学科研苗圃工程项目(MP2020-16)

Study on intercellular communication and key genes of smooth muscle cells in human coronary atherosclerosis based on single cell sequencing technology

SI Chunying¹^,²(), WANG Jianru², LI Xiaohui²(), WANG Yongxia¹^,², GUAN Huaimin²

^1.The First Clinical Medical College (College of Integrated Traditional Chinese and Western Medicine), Henan University of Chinese Medicine, Zhengzhou 450003, China
^2.Heart Center/National Regional (Traditional Chinese Medicine) Cardiovascular Diagnosis and Treatment Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450003, China

Received:2023-05-19 Accepted:2023-12-11 Online:2024-02-28 Published:2024-03-25
Contact: LI Xiaohui E-mail:chunyingsi1987@163.com;478103511@qq.com
Supported by:
Henan Natural Science Foundation Youth Fund Project(232300420273);Henan Province Medical Science and Technology Research Plan Jointly Construction Project(LHGJ20230690);Youth Fund Project of National Natural Science Foundation of China(82205021);Henan Province Science and Technology Research Project(212102311083);Research Nursery Engineering Project of Henan University of Chinese Medicine(MP2020-16)

摘要/Abstract

摘要：

目的·利用单细胞RNA测序技术（single-cell?RNA?sequencing，scRNA-Seq）阐释冠状动脉粥样硬化（coronary atherosclerosis，CA）的细胞通信景观，挖掘主导细胞亚群及其关键基因。方法·下载GSE131778数据集并进行预处理、质控、降维聚类及注释；利用CellChat包进行细胞通信分析，识别主导细胞亚群。利用FindAllMarker函数，筛选主导细胞亚群与其他细胞亚群间的差异表达基因（differentially expressed genes，DEGs），并构建其蛋白相互作用（protein-protein interaction，PPI）网络，将Degree算法排序前五位的DEGs作为关键基因。将关键基因与CellChat分析出的细胞通信网络进行匹配和挖掘，获取关键基因参与的配体-受体对（ligand-receptor pair，L-R）及其介导的信号通路，并对结果进行可视化。构建动脉粥样硬化小鼠模型，并利用反转录聚合酶链式反应检测关键基因在颈动脉粥样硬化病变处的表达情况。结果·在CA病变处共鉴定出11个细胞亚群，包括平滑肌细胞、内皮细胞、巨噬细胞、单核细胞等。细胞通信分析结果显示，CellChat在11个细胞亚群中检测到70对显著的L-R和26条相关的信号通路；平滑肌细胞处于通信活跃状态，与其他细胞亚群间相互作用的次数和强度最显著，是主导细胞亚群。DEGs筛选结果显示，平滑肌细胞亚群和其他细胞亚群之间共有206个DEGs，其中ITGB2、PTPRC、CCL2、DCN、IGF1被识别为关键基因。关键基因介导的细胞通信分析结果显示：CCL2与ACKR1形成L-R，通过介导CCL信号通路参与平滑肌细胞与内皮细胞间的通信网络；ITGB2分别与ITGAM、ITGAX组成受体复合物，再与C3形成L-R介导补体信号通路，参与平滑肌细胞与巨噬细胞、单核细胞间的通信网络。动物实验对关键基因的验证结果同生物信息学分析的结果一致。结论·平滑肌细胞在CA病理过程中是主导细胞，与其他细胞间有广泛的通信网络，可通过CCL2-ACKR1、C3-（ITGAM+ITGB2）和C3-（ITGAX+ITGB2）介导的CCL和补体信号通路，与内皮细胞、巨噬细胞和单核细胞构建细胞通信网络。

关键词: 冠状动脉粥样硬化, 单细胞RNA测序, 平滑肌细胞, 细胞通信

Abstract:

Objective ·To use single-cell RNA sequencing (scRNA-Seq) technology to interpret the cellular communication landscape of coronary atherosclerosis (CA), and to explore the dominant cell subsets and their key genes. Methods ·The GSE131778 data set was downloaded and preprocessed, and quality controlling, dimension reduction clustering and annotation were carried out. Then cell communication analysis was conducted by using CellChat package to identify dominant cell subsets. The FindAllMarker function was used to screen differentially expressed genes (DEGs) between the dominant cell subpopulation and other cell subpopulations, and its protein-protein interaction (PPI) network was constructed. The DEGs ranked in the top five of the Degree algorithm were taken as key genes. Then, the key genes were matched and mined with the cell communication network analyzed by CellChat to obtain the ligand-receptor pairs (L-R) and the signal pathways mediated by the key genes, and the results were visualized. At the same time, the atherosclerosis mouse model was constructed and RT-PCR was used to detect the expression of key genes in carotid atherosclerosis lesions. Results ·A total of 11 cell subsets were identified in CA lesions, including smooth muscle cells, endothelial cells, macrophages, monocytes, etc. Cell communication results showed that CellChat detected 70 significant L-R and 26 related signal pathways in 11 cell subsets. Smooth muscle cell was the dominant cell subgroup with the most significant interaction frequency and intensity with other cell subgroups in the active state of communication. The results of DEGs screening showed that there were 206 DEGs between smooth muscle cell subsets and other cell subsets, among which ITGB2, PTPRC, CCL2, DCN and IGF1 were identified as key genes. The results of cell communication mediated by key genes showed that CCL2 and ACKR1 formed L-R and participated in the communication network between smooth muscle cells and endothelial cells through mediating CCL signaling pathway. ITGB2 formed receptor complexes withITGAM and ITGAX respectively, and then formed L-R with C3 to mediate the complement signal pathway, participating in the communication network among smooth muscle cells, macrophages and monocytes. The validation results of hub genes in animal experiments were consistent with the results of bioinformatics analysis. Conclusion ·Smooth muscle cells are the dominant cells in the pathological process of CA, and have extensive communication networks with other cells. They can construct cellular communication networks with endothelial cells, macrophages and monocytes through CCL and complement signaling pathways mediated by CCL2-ACKR1, C3-(ITGAM+ITGB2) and C3-(ITGAX+ITGB2).

Key words: coronary atherosclerosis, single-cell RNA sequencing (scRNA-Seq), smooth muscle cell, cellular communication

中图分类号:

R543.3

司春婴, 王建茹, 李晓辉, 王永霞, 关怀敏. 基于单细胞测序技术解析冠状动脉粥样硬化患者平滑肌细胞的细胞间通信及关键基因[J]. 上海交通大学学报（医学版）, 2024, 44(2): 169-182.

SI Chunying, WANG Jianru, LI Xiaohui, WANG Yongxia, GUAN Huaimin. Study on intercellular communication and key genes of smooth muscle cells in human coronary atherosclerosis based on single cell sequencing technology[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(2): 169-182.

图/表 10

表1 RT-PCR引物序列

Tab 1 Primer sequence for RT-PCR

Primer	Sequence (5'→3')	Length/bp
ITGB2-F	ACCTCATGGATCTCTCCTACTC	274
ITGB2-R	CCGACCTCTGTCTGAAACTG	274
PTPRC-F	AGTCTCTACGCAAAGCACGG	254
PTPRC-R	AGCACTATTGGTAGGCTCCG	254
CCL2-F	GCTGACCCCAAGAAGGAATG	183
CCL2-R	TGAGGTGGTTGTGGAAAAGG	183
DCN-F	AATCCCTTATGACCCTGACA	275
DCN-R	TTTCCAACTTCACGAGAGGT	275
IGF1-F	GATGCTCTTCAGTTCGTGTG	259
IGF1-R	GCTTCGTTTTCTTGTTTGTC	259
GAPDH-F	CCTTCCGTGTTCCTAC	152
GAPDH-R	GACAACCTGGTCCTCA	152

图1 GSE131778数据集样本的质控结果Note：A. Number of cell genes in the sample. B. Number of transcript sequencing counts in the sample. C. The proportion of mitochondria in all the cells in the sample. D. The top 1 500 mutated genes with high intercellular standard deviation.

Fig1 Quality control results for samples from the GSE131778 dataset

图2 GSE131778数据集中样本的降维聚类及注释结果Note：A.The distribution of cells in the sample in PC1 and PC2. B. P value for each PC. C. t-SNE plot of clustering distribution of 18 cell subpopulations. D. t-SNE diagram of the distribution of cell subpopulations after annotation. NK cell—nature killer cell; DC—dendritic cell.

Fig 2 Dimension reduction clustering and annotation results for samples in the GSE131778 dataset

图3 CA病变处的细胞通信网络Note：A.Communication network diagram of the number of interactions among different cell clusters. B.Communication network diagram of interaction strength among different cell clusters. C. Communication network diagram of the interaction strength between a single cell cluster and other clusters. The color of the dots represents different cell clusters. The size of the dots represents the number of cells contained in the cell cluster, and the larger the dots, the more cells there are. The line represents the interaction relationship among the clusters, and the color represents the signal sent from the cluster as the sender to the cluster as the receiver. The thickness of the line represents the number of interactions (strength) among the clusters, and the thicker the line, the more interactions (strength) there are.

Fig 3 Cellular communication network at CA lesions

图4 平滑肌细胞DEGs的筛选及其富集分析Note：A.Volcano plot of DEGs in smooth muscle cells (dots represent genes, black represents genes with no differential expression, red represents upregulated DEGs, and blue represents downregulated DEGs). B. Bubble plots for GO enrichment analysis of DEGs. C. Circle diagram of KEGG enrichment analysis of DEGs.

Fig 4 Screening of DEGs in smooth muscle cells and their enrichment analysis

图5 平滑肌细胞关键基因的筛选结果Note： A. PPI network diagram of smooth muscle cell DEGs, with red circles representing upregulated DEGs and green triangles representing downregulated DEGs. B. PPI diagram of 5 hub genes. C. Circle diagram of chromosomal positions of hub genes. D. Bubble plot of 5 hub genes expressed in 11 clusters.

Fig 5 Results of screening for hub genes in smooth muscle cells

表2 关键基因介导的细胞间信号通路

Tab 2 Hub genes-mediated cell signaling pathway

Source	Target	Ligand	Receptor	Probability	Interaction name	Pathway	Annotation	Evidence (PMID)
Chondrocyte	Endothelial cell	CCL2	ACKR1	0.053	CCL2-ACKR1	CCL	Secreted signaling	26740381
Macrophage	Endothelial cell	CCL2	ACKR1	0.042	CCL2-ACKR1	CCL	Secreted signaling	26740381
Monocyte	Endothelial cell	CCL2	ACKR1	0.047	CCL2-ACKR1	CCL	Secreted signaling	26740381
Neuron	Endothelial cell	CCL2	ACKR1	0.060	CCL2-ACKR1	CCL	Secreted signaling	26740381
Smooth muscle cell	Endothelial cell	CCL2	ACKR1	0.244	CCL2-ACKR1	CCL	Secreted signaling	26740381
Tissue stem cell	Endothelial cell	CCL2	ACKR1	0.021	CCL2-ACKR1	CCL	Secreted signaling	26740381
Macrophage	Macrophage	C3	ITGAM_ITGB2	0.004	C3-(ITGAM+ITGB2)	Complement	Secreted signaling	16234578
Smooth muscle cell	Macrophage	C3	ITGAM_ITGB2	0.040	C3-(ITGAM+ITGB2)	Complement	Secreted signaling	16234578
Macrophage	Monocyte	C3	ITGAM_ITGB2	0.005	C3-(ITGAM+ITGB2)	Complement	Secreted signaling	16234578
Smooth muscle cell	Monocyte	C3	ITGAM_ITGB2	0.046	C3-(ITGAM+ITGB2)	Complement	Secreted signaling	16234578
Macrophage	Macrophage	C3	ITGAX_ITGB2	0.004	C3-(ITGAX+ITGB2)	Complement	Secreted signaling	16234578
Smooth muscle cell	Macrophage	C3	ITGAX_ITGB2	0.040	C3-(ITGAX+ITGB2)	Complement	Secreted signaling	16234578

图6 关键基因介导的细胞间通信Note： A. Cellular communication network diagram mediated by CCL signaling pathway. B. Heat map of cell action types in the CCL signaling pathway. C. Bar chart of the contribution of L-R in the CCL signaling pathway. D. CCL2-ACKR1-mediated cellular communication network diagram. E. Cellular communication network diagram mediated by complement signaling pathway. F. Heat map of cellular action types in complement signaling pathways. G. Bar graph of the contribution of L-R in the complement signaling pathway. H. C3-(ITGAM+ITGB2)-mediated cellular communication network diagram. I. C3-(ITGAX+ITGB2)-mediated cellular communication network diagram.

Fig 6 Hub genes-mediated cellular communication

图7 小鼠主动脉组织H-E染色

Fig 7 H-E staining of aortic tissue of mice

表3 各组小鼠关键基因mRNA表达水平（x±s， n=3）

Tab 3 mRNA expression levels of hub genes in each group of mice （x±s， n=3）

Group	ITGB2	PTPRC	CCL2	DCN	IGF1
Control	1.04±0.34	1.00±0.06	1.01±0.19	1.01±0.15	1.00±0.06
AS	0.45±0.11^①	0.21±0.01^②	2.19±0.57^③	1.57±0.11^④	4.24±1.14^⑤

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基于单细胞测序技术解析冠状动脉粥样硬化患者平滑肌细胞的细胞间通信及关键基因

Study on intercellular communication and key genes of smooth muscle cells in human coronary atherosclerosis based on single cell sequencing technology

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