Zhang Qianyuan, Cai Ziwen, Zhang Yongqiao
Department of General Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
Sci Rep. 2025 May 30;15(1):18964. doi: 10.1038/s41598-025-00260-7.
Fibroblasts play a crucial role in the development and progression of heart failure in many heart-related diseases. However, the contributions of fibroblast and its subtypes to the pathogenesis of ischemic cardiomyopathy (ICM) remain unclear. In this study, we analyzed single-nucleus RNA sequencing data from cardiac tissues of seven ICM patients with heart failure and eight control subjects. Our findings indicate that, compared to controls, fibroblasts from ICM patients exhibit dysregulation of genes associated with cell-substrate adhesion and matrix or collagen fibril organization. We further identified five fibroblast subtypes, designated as FB1 through FB5, with FB3 exhibiting the highest frequency in ICM. Pseudotime trajectory analysis further revealed an evolutionary progression of fibroblasts from FB1/FB2 toward FB3. Differential gene expression analysis of FB3 highlighted several subtype-specific genes, such as NTM, THBS4, NRK, NAV2, and PLA2G5. Furthermore, intercellular interaction analysis revealed that FB3 exhibits weakened interactions with other cells under ICM. Specifically, signaling interactions involving ANGPTL and COLLAGEN are reduced, whereas pathways mediated by THBS, NRXN, and APP are strengthened. These results provide valuable insights into the fibroblast microenvironment and elucidate the pathological mechanisms underlying ICM, laying a theoretical foundation for the identification of novel therapeutic targets.
成纤维细胞在许多与心脏相关的疾病中，对心力衰竭的发生和发展起着关键作用。然而，成纤维细胞及其亚型对缺血性心肌病（ICM）发病机制的贡献仍不清楚。在本研究中，我们分析了7例患有心力衰竭的ICM患者和8例对照受试者心脏组织的单核RNA测序数据。我们的研究结果表明，与对照组相比，ICM患者的成纤维细胞表现出与细胞-底物黏附以及基质或胶原纤维组织相关基因的失调。我们进一步鉴定出五种成纤维细胞亚型，命名为FB1至FB5，其中FB3在ICM中出现的频率最高。伪时间轨迹分析进一步揭示了成纤维细胞从FB1/FB2向FB3的进化过程。FB3的差异基因表达分析突出了几个亚型特异性基因，如NTM、THBS4、NRK、NAV2和PLA2G5。此外，细胞间相互作用分析表明，在ICM条件下，FB3与其他细胞的相互作用减弱。具体而言，涉及ANGPTL和胶原蛋白的信号相互作用减少，而由THBS、NRXN和APP介导的途径增强。这些结果为成纤维细胞微环境提供了有价值的见解，并阐明了ICM的病理机制，为鉴定新的治疗靶点奠定了理论基础。
