Fibroblasts—The emerging therapeutic target of the cardiovascular system?

Recent advances in single-cell RNA sequencing have uncovered fibroblasts' heterogeneous and plastic nature across the cardiovascular system, highlighting their diverse roles beyond extracellular matrix production, including inflammatory signaling and phenotypic switching. This review synthesizes insights into fibroblast heterogeneity and modulation in healthy and diseased heart and vasculature states. It emphasizes the lack of a consensus nomenclature for fibroblast subtypes, attributing this gap to the need for large-scale meta-analyses and extensive validation studies. The emerging understanding of fibroblast subpopulations and their shared markers across cardiac and vascular tissues introduces therapeutic potential and safety concerns. Although preclinical studies targeting fibroblasts in the heart using gene silencing, editing, or epigenetic modulation show promise, comparable vascular interventions remain limited. Therapeutic strategies could benefit from improved fibroblast-specific markers to minimize off-target effects and enhance precision. Ultimately, the review advocates for refined characterization and nomenclature of fibroblast subsets to better exploit their therapeutic potential, while acknowledging the challenges posed by their overlapping phenotypes and diverse functionalities within the cardiovascular system. SIGNIFICANCE STATEMENT: Fibroblasts are a heterogeneous cell type with critical roles in cardiovascular homeostasis and disease. We explore advances in understanding fibroblast diversity and therapeutic potential. We underscore the importance of precision in cardiovascular disease through a consensus on nomenclature and marker specificity.