Single-cell RNA sequencing reveals the potential role of Postn(+) fibroblasts in promoting the progression of myocardial fibrosis after myocardial infarction.

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.