Chimenti Isotta, Pagano Francesca, Cozzolino Claudia, Icolaro Francesca, Floris Erica, Picchio Vittorio
Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00185 Latina, Italy.
Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Italy.
Int J Mol Sci. 2025 Jun 19;26(12):5882. doi: 10.3390/ijms26125882.
Cardiac fibrosis is a key physiopathological process underlying the progression of virtually all heart diseases and related conditions, including myocardial infarction, pressure overload, and heart failure. Once regarded as a homogeneous and passive population, cardiac fibroblasts are now recognized as highly heterogeneous and dynamic, comprising distinct subpopulations with specialized molecular and functional identities. These subpopulations include resident fibroblasts, activated myofibroblasts, matrifibrocytes, inflammatory fibroblasts, and senescent fibroblasts, each contributing uniquely to extracellular matrix (ECM) remodeling, cytokine secretion, and intercellular crosstalk. Recent advances in single-cell transcriptomics, lineage tracing, and epigenetic profiling have revealed the plasticity and phenotypic transitions of cardiac fibroblasts in both physiological and pathological contexts. This review synthesizes current knowledge on fibroblast diversity in the adult heart, including their embryological origins and anatomical distribution, and explores how these insights could guide the development of precision anti-fibrotic therapies. We discuss a selection of emerging therapeutic strategies, including subtype-specific targeting (e.g., anti-POSTN, anti-IL1β), modulation of key signaling pathways (e.g., TGF-β, Wnt, Notch), with a brief mention also of novel approaches based on non-coding RNAs and epigenetic regulators. A better understanding of cardiac fibroblast heterogeneity holds significant potential for the design of more specific cell-type and context-tailored interventions, moving toward more effective and personalized treatments for cardiac fibrosis and its sequelae.
心脏纤维化是几乎所有心脏病及相关病症（包括心肌梗死、压力过载和心力衰竭）进展的关键病理生理过程。心脏成纤维细胞曾被视为同质且被动的群体，如今被认为具有高度异质性和动态性，由具有特定分子和功能特征的不同亚群组成。这些亚群包括驻留成纤维细胞、活化肌成纤维细胞、基质成纤维细胞、炎性成纤维细胞和衰老成纤维细胞，它们各自对细胞外基质（ECM）重塑、细胞因子分泌和细胞间串扰有独特贡献。单细胞转录组学、谱系追踪和表观遗传谱分析的最新进展揭示了心脏成纤维细胞在生理和病理情况下的可塑性和表型转变。本综述综合了目前关于成年心脏中成纤维细胞多样性的知识，包括它们的胚胎起源和解剖分布，并探讨这些见解如何指导精准抗纤维化疗法的开发。我们讨论了一系列新兴治疗策略，包括亚型特异性靶向（如抗POSTN、抗IL1β）、关键信号通路的调节（如TGF-β、Wnt、Notch），还简要提及了基于非编码RNA和表观遗传调节因子的新方法。更好地理解心脏成纤维细胞的异质性对于设计更具特异性的细胞类型和针对具体情况的干预措施具有巨大潜力，朝着更有效和个性化地治疗心脏纤维化及其后遗症迈进。
