Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction.
Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction.
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DOI：
10.1161/circulationaha.119.044557
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发表时间：
2020-11-10
期刊：
影响因子：
37.8
通讯作者：
Prósper F
中科院分区：
文献类型：
--
作者：
Ruiz-Villalba A;Romero JP;Hernández SC;Vilas-Zornoza A;Fortelny N;Castro-Labrador L;San Martin-Uriz P;Lorenzo-Vivas E;García-Olloqui P;Palacio M;Gavira JJ;Bastarrika G;Janssens S;Wu M;Iglesias E;Abizanda G;de Morentin XM;Lasaga M;Planell N;Bock C;Alignani D;Medal G;Prudovsky I;Jin YR;Ryzhov S;Yin H;Pelacho B;Gomez-Cabrero D;Lindner V;Lara-Astiaso D;Prósper F
心脏成纤维细胞（CF）在与不同类型的纤维化相关的心室重塑过程中起着重要作用。最近的研究表明，成纤维细胞对心脏损伤的反应并不均匀。由于有限的一组真正的成纤维细胞标志物，对心脏损伤的成纤维细胞群体异质性的适当表征仍然缺失。本研究的目的是明确心室重构过程中CF的异质性及其调节功能的潜在机制。通过单细胞和批量RNA-seq、ATAC-seq和功能测定表征心肌梗死（MI）后的胶原1 α1-GFP+ CF。使用批量RNA-seq研究猪和患者样品。我们确定并表征了小鼠MI后出现的独特CF亚群。这些活化的成纤维细胞表现出明显的促纤维化特征，表达高水平的含胶原蛋白三重受阻重复序列1（Cthrc 1）并定位于瘢痕中。非经典TGF-β信号传导和包括SOX 9在内的不同转录因子是介导其对心脏损伤的反应的重要调节因子。此外，CTHRC 1的缺乏导致心室破裂导致明显的致死性。最后，在MI猪模型和MI和扩张型心肌病患者的心脏组织中鉴定了具有相似转录组的CF群体。我们报道了心肌梗死过程中CF的异质性及其动态变化，并重新定义了CF对心肌损伤的反应和参与心肌重塑。我们的研究将Cthrc 1确定为愈合疤痕过程的新型调节剂，并将其作为未来翻译研究的目标。
Cardiac fibroblasts (CF) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Due to the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is still missing. The purpose of this study was to define the CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate their function. Collagen1α1-GFP+ CF were characterized after myocardial infarction (MI) by single-cell and bulk RNA-seq, ATAC-seq and functional assays. Swine and patient samples were studied using bulk RNA-seq. We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear pro-fibrotic signature, express high levels of Collagen Triple Helix Repeat Containing 1 (Cthrc1) and localize into the scar. Non-canonical TGF-β signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Moreover, the absence of CTHRC1 results in pronounced lethality due to ventricular rupture. Finally, a population of CF with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy. We report CF heterogeneity, their dynamics during the course of MI and redefine the CF that respond to cardiac injury and participate in myocardial remodeling. Our study identifies Cthrc1 as a novel regulator of the healing scar process, and as a target for future translational studies.