Cardiac pericytes mediate the remodeling response to myocardial infarction.
Cardiac pericytes mediate the remodeling response to myocardial infarction.
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DOI：
10.1172/jci162188
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发表时间：
2023-05-15
影响因子：
15.9
通讯作者：
Ardehali, Reza
中科院分区：
文献类型：
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作者：
Quijada, Pearl;Park, Shuin;Zhao, Peng;Kolluri, Kamal S. S.;Wong, David;Shih, Kevin D.;Fang, Kai;Pezhouman, Arash;Wang, Lingjun;Daraei, Ali;Tran, Matthew D.;Rathbun, Elle M.;Villar, Kimberly N. Burgos;Garcia-Hernandez, Maria L.;Pham, Thanh T. D.;Lowenstein, Charles J.;Iruela-Arispe, M. Luisa;Carmichael, S. Thomas;Small, Eric M.;Ardehali, Reza
尽管周细胞在心脏微血管系统中普遍存在，但它们在缺血诱导的重塑过程中的作用仍不清楚。我们使用多个谱系追踪小鼠模型，发现周细胞迁移到损伤部位并表达促纤维化基因，与心肌梗死（MI）后血管渗漏增加一致。心肌梗死后不同时间点的心肌周细胞的单细胞RNA-Seq显示了与血管通透性、细胞外基质产生、基底膜降解和TGF-β信号传导相关的基因的时间调节诱导。在表达硫酸软骨素蛋白聚糖4（表达Cspg 4）的细胞中删除TGF-β受体1可减少MI后的纤维化，导致心脏射血分数的短暂改善。此外，Cspg 4表达细胞的基因消融导致MI后第二周的过度血管通透性、心脏功能下降和死亡率增加。这些数据揭示了心脏周细胞在控制血管稳态和急性缺血性损伤后的纤维化反应中的重要作用，这些信息将有助于指导新策略的发展，以保持血管完整性和减弱病理性心脏重塑。
Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-β signaling. Deleting TGF-β receptor 1 in chondroitin sulfate proteoglycan 4–expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac ejection fraction. Furthermore, genetic ablation of Cspg4-expressing cells resulted in excessive vascular permeability, a decline in cardiac function, and increased mortality in the second week after MI. These data reveal an essential role for cardiac pericytes in the control of vascular homeostasis and the fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate pathological cardiac remodeling.