Nie Wenyang, Zhao Zhijie, Xiahou Zhikai, Zhang Jingwen, Liu Yuhang, Wang Yong, Wang Zhen
First Clinical Medical College, Shandong University of Traditional Chinese Medicine, 16369 Jingshi Rd, Jinan, 250014, China.
Department of Plastic and Reconstructive Surgery, Shanghai ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Rd, Shanghai, 200011, China.
Sci Rep. 2025 Jul 1;15(1):22390. doi: 10.1038/s41598-025-04990-6.
Myocardial infarction (MI) is a life-threatening coronary artery-related pathology characterized by sudden cardiac death, often leading to cardiac fibrosis and heart failure (HF). Despite advances in emergency care and treatment measures such as percutaneous coronary intervention (PCI), the mortality rate due to HF following MI remains high, making it the leading cause of death in MI patients. While cardiac fibroblasts are known to be closely associated with the adverse outcomes of cardiac fibrosis and HF post-MI, the cellular landscape of fibroblasts after MI and their role in myocardial fibrosis and HF progression has not been fully explored. Our study identified a key, highly proliferative fibroblast subpopulation, named C1 Postn + Fibroblasts, which showed high myocardial fibrosis scores. C1 Postn + Fibroblasts were primarily located at the early stage of the pseudo-time trajectory and exhibited high stemness. These cells interact with EndoCs, ECs, and macrophages through the Cxcl12-Ackr3, Ptn-Ncl, and Mdk-Lrp1 signaling pathways, thereby influencing myocardial fibrosis progression. Additionally, Tead1 and Hdac2 were found to be key and highly active transcription factors in this subpopulation. In vitro experiments showed that knocking down Postn significantly decreased the activity of cardiac fibroblasts, inhibited their migration and adhesion capabilities, and induced apoptosis. This subpopulation may be more sensitive to post-MI adverse events, while other subpopulations may exhibit more inhibited responses. Stemness genes Ctnnb1 and Hifla, as well as oxidative phosphorylation and glutathione metabolism pathways, should be closely monitored in efforts to prevent myocardial fibrosis post-MI. The Cxcl12-Ackr3, Ptn-Ncl, and Mdk-Lrp1 pathways may represent potential routes to disrupt the key interactions between C1 Postn + Fibroblasts and EndoCs, ECs, and macrophages. Tead1 and Hdac2 may be potential targets for inhibiting myocardial fibrosis and preventing adverse outcomes of MI after further experimental verification. The gene Postn, expressed in C1 Postn + Fibroblasts, may contribute to the inhibition of abnormal fibroblast activation post-MI. These findings open new perspectives for the prevention and treatment of myocardial fibrosis after MI and the prevention of its progression to HF.
心肌梗死（MI）是一种危及生命的冠状动脉相关病理状态，其特征为心源性猝死，常导致心脏纤维化和心力衰竭（HF）。尽管在急诊护理和经皮冠状动脉介入治疗（PCI）等治疗措施方面取得了进展，但MI后因HF导致的死亡率仍然很高，使其成为MI患者的主要死因。虽然已知心脏成纤维细胞与MI后心脏纤维化和HF的不良后果密切相关，但MI后成纤维细胞的细胞图谱及其在心肌纤维化和HF进展中的作用尚未得到充分探索。我们的研究确定了一个关键的、高度增殖的成纤维细胞亚群，名为C1 Postn+成纤维细胞，其心肌纤维化评分较高。C1 Postn+成纤维细胞主要位于伪时间轨迹的早期阶段，并表现出高干性。这些细胞通过Cxcl12-Ackr3、Ptn-Ncl和Mdk-Lrp1信号通路与内皮细胞（EndoCs）、内皮细胞（ECs）和巨噬细胞相互作用，从而影响心肌纤维化的进展。此外，发现Tead1和Hdac2是该亚群中关键且高度活跃的转录因子。体外实验表明，敲低Postn可显著降低心脏成纤维细胞的活性，抑制其迁移和黏附能力，并诱导细胞凋亡。该亚群可能对MI后的不良事件更敏感，而其他亚群可能表现出更多的抑制反应。在预防MI后心肌纤维化的努力中，应密切监测干性基因Ctnnb1和Hifla以及氧化磷酸化和谷胱甘肽代谢途径。Cxcl12-Ackr3、Ptn-Ncl和Mdk-Lrp1途径可能代表破坏C1 Postn+成纤维细胞与EndoCs、ECs和巨噬细胞之间关键相互作用的潜在途径。经过进一步实验验证后，Tead1和Hdac2可能是抑制心肌纤维化和预防MI不良后果的潜在靶点。在C1 Postn+成纤维细胞中表达的基因Postn可能有助于抑制MI后成纤维细胞的异常激活。这些发现为MI后心肌纤维化的预防和治疗以及预防其进展为HF开辟了新的视角。
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