Single-Cell Transcriptomic Analysis Reveals Myocardial Fibrosis Mechanism of Doxorubicin-Induced Cardiotoxicity

IF 1.2 4区 医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS
Yige Huyan, Xiao Chen, Yuan Chang, Xiumeng Hua, Xuexin Fan, Dan Shan, Zhenyu Xu, Menghao Tao, Hang Zhang, Sheng Liu, Jiangping Song
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引用次数: 0

Abstract

Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the specific cellular and molecular mediators driving doxorubicin-induced cardiac fibrosis, and the relative impact of different cell populations on cardiac fibrosis, remain unclear.

This study aimed to explore the mechanism of doxorubicin-induced cardiotoxicity and myocardial fibrosis and to find potential therapeutic targets. Single-cell RNA sequencing was used to analyze the transcriptome of non-cardiomyocytes from normal and doxorubicin-induced chronic cardiotoxicity in mouse model heart tissue.

We established a mouse model of doxorubicin-induced cardiotoxicity with a well-defined fibrotic phenotype. Analysis of single-cell sequencing results showed that fibroblasts were the major origin of extracellular matrix in doxorubicin-induced myocardial fibrosis. Further resolution of fibroblast subclusters showed that resting fibroblasts were converted to matrifibrocytes and then to myofibroblasts to participate in the myocardial remodeling process in response to doxorubicin treatment. Ctsb expression was significantly upregulated in fibroblasts after doxorubicin-induced.

This study provides a comprehensive map of the non-cardiomyocyte landscape at high resolution, reveals multiple cell populations contributing to pathological remodeling of the cardiac extracellular matrix, and identifies major cellular sources of myofibroblasts and dynamic gene-expression changes in fibroblast activation. Finally, we used this strategy to detect potential therapeutic targets and identified Ctsb as a specific target for fibroblasts in doxorubicin-induced myocardial fibrosis.

单细胞转录组分析揭示多柔比星诱发心脏毒性的心肌纤维化机制
心肌纤维化是多柔比星诱导的慢性心脏毒性的病理特征,严重影响肿瘤患者的预后。本研究旨在探索多柔比星诱导心脏毒性和心肌纤维化的机制,并寻找潜在的治疗靶点。我们建立了一个多柔比星诱导的心脏毒性小鼠模型,该模型具有明确的纤维化表型。单细胞测序结果分析表明,在多柔比星诱导的心肌纤维化中,成纤维细胞是细胞外基质的主要来源。对成纤维细胞亚群的进一步解析显示,静止的成纤维细胞在多柔比星治疗后转化为亚纤维细胞,然后转化为肌成纤维细胞,参与心肌重塑过程。这项研究以高分辨率提供了非心肌细胞的全面图谱,揭示了导致心脏细胞外基质病理性重塑的多种细胞群,并确定了成肌纤维细胞的主要细胞来源以及成纤维细胞活化过程中的动态基因表达变化。最后,我们利用这一策略检测了潜在的治疗靶点,并确定 Ctsb 是多柔比星诱导的心肌纤维化中成纤维细胞的特异性靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International heart journal
International heart journal 医学-心血管系统
CiteScore
2.50
自引率
6.70%
发文量
148
审稿时长
6-12 weeks
期刊介绍: Authors of research articles should disclose at the time of submission any financial arrangement they may have with a company whose product figures prominently in the submitted manuscript or with a company making a competing product. Such information will be held in confidence while the paper is under review and will not influence the editorial decision, but if the article is accepted for publication, the editors will usually discuss with the authors the manner in which such information is to be communicated to the reader.
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