Single-Cell RNA Sequencing of Coronary Perivascular Adipose Tissue From End-Stage Heart Failure Patients Identifies SPP1(+) Macrophage Subpopulation as a Target for Alleviating Fibrosis.
Single-Cell RNA Sequencing of Coronary Perivascular Adipose Tissue From End-Stage Heart Failure Patients Identifies SPP1(+) Macrophage Subpopulation as a Target for Alleviating Fibrosis.
复制标题
终末期心力衰竭患者冠状动脉血管周围脂肪组织的单细胞RNA测序证实SPP1（+）巨噬细胞亚群作为减轻纤维化的靶点。
DOI：
10.1161/atvbaha.123.319828
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发表时间：
2023-11
影响因子：
8.7
通讯作者：
Song, Jiangping
中科院分区：
文献类型：
--
作者：
Fu, Mengxia;Shu, Songren;Peng, Zhiming;Liu, Xiaorui;Chen, Xiao;Zeng, Zhiwei;Yang, Yicheng;Cui, Hao;Zhao, Ruojin;Wang, Xiaohu;Du, Leilei;Wu, Min;Feng, Wei;Song, Jiangping
关键词：
血管周围脂肪组织(PVAT)对血管内稳态至关重要，PVAT功能障碍与动脉粥样硬化斑块负荷增加有关。但在冠状动脉粥样硬化中，冠脉PVAT功能障碍的机制仍不清楚。我们对3组终末期心力衰竭的心脏移植受者的冠脉PVAT间质血管部分进行了单细胞RNA测序，其中包括3例非梗阻性冠状动脉粥样硬化患者、3例阻塞性冠状动脉粥样硬化患者和4例非动脉粥样硬化对照组。应用生物信息学对细胞群体进行注释，描绘细胞发育轨迹和相互作用，并从细胞和分子水平探讨3组冠脉PVAT之间的差异。通过病理染色、实时定量聚合酶链式反应和体外研究来验证关键发现。从67个人冠脉 936细胞中鉴定出10种细胞类型。与非动脉粥样硬化的冠状动脉相比，动脉粥样硬化周围的PVAT中聚集了几个细胞亚群，包括SPP1+(分泌型磷蛋白1)巨噬细胞和纤维形成脂肪前体细胞。动脉粥样硬化周围PVAT纤维化百分率增高，且与冠状动脉狭窄程度呈正相关。细胞相互作用分析表明，SPP1+巨噬细胞分泌的骨桥蛋白(OPN)与成纤维脂肪前体细胞上的CD44(分化簇44)/整合素相互作用。值得注意的是，相关分析发现，PVAT中高水平的SPP1与更严重的纤维化程度和更高的冠状动脉狭窄程度相关。体外研究表明，动脉粥样硬化冠脉PVAT的条件培养液可促进成纤维脂肪前体细胞的迁移和增殖，而CD44或整合素的阻断可阻止这种作用。SPP1+巨噬细胞聚集在粥样硬化冠状动脉周围的PVAT中，通过OPN-CD44/整合素的相互作用促进成纤维脂肪前体细胞的迁移和增殖，从而加重冠状动脉PVAT的纤维化，并与冠状动脉狭窄负荷呈正相关。因此，冠脉PVAT内SPP1+巨噬细胞可能参与了冠状动脉粥样硬化的进展。
Perivascular adipose tissue (PVAT) is vital for vascular homeostasis, and PVAT dysfunction is associated with increased atherosclerotic plaque burden. But the mechanisms underlining coronary PVAT dysfunction in coronary atherosclerosis remain elusive. We performed single-cell RNA sequencing of the stromal vascular fraction of coronary PVAT from 3 groups of heart transplant recipients with end-stage heart failure, including 3 patients with nonobstructive coronary atherosclerosis, 3 patients with obstructive coronary artery atherosclerosis, and 4 nonatherosclerosis control subjects. Bioinformatics was used to annotate the cellular populations, depict the cellular developmental trajectories and interactions, and explore the differences among 3 groups of coronary PVAT at the cellular and molecular levels. Pathological staining, quantitative real-time polymerase chain reaction, and in vitro studies were performed to validate the key findings. Ten cell types were identified among 67 936 cells from human coronary PVAT. Several cellular subpopulations, including SPP1+ (secreted phosphoprotein 1) macrophages and profibrotic fibroadipogenic progenitor cells, were accumulated in PVAT surrounding atherosclerotic coronary arteries compared with nonatherosclerosis coronary arteries. The fibrosis percentage was increased in PVAT surrounding atherosclerotic coronary arteries, and it was positively associated with the grade of coronary artery stenosis. Cellular interaction analysis suggested OPN (osteopontin) secreted by SPP1+ macrophages interacted with CD44 (cluster of differentiation 44)/integrin on fibroadipogenic progenitor cells. Strikingly, correlation analyses uncovered that higher level of SPP1 in PVAT correlates with a more severe fibrosis degree and a higher coronary stenosis grade. In vitro studies showed that conditioned medium from atherosclerotic coronary PVAT promoted the migration and proliferation of fibroadipogenic progenitor cells, while such effect was prevented by blocking CD44 or integrin. SPP1+ macrophages accumulated in the PVAT surrounding atherosclerotic coronary arteries, and they promoted the migration and proliferation of fibroadipogenic progenitor cells via OPN-CD44/integrin interaction and thus aggravated the fibrosis of coronary PVAT, which was positively correlated to the coronary stenosis burden. Therefore, SPP1+ macrophages in coronary PVAT may participate in the progression of coronary atherosclerosis.