Bridging the Translational Gap: Rethinking Smooth Muscle Cell Plasticity in Atherosclerosis Through Human-Relevant In Vitro Models.

While vascular smooth muscle cell (SMC) plasticity is increasingly recognised as a critical driver of atherosclerosis progression, most mechanistic insights derive from murine models that fail to fully capture the diversity and complexity of human SMC phenotypes. This creates a translational gap in our understanding of disease-relevant cell states. Human single-cell and genetic studies reveal a broader spectrum of SMC phenotypes, many of which remain uncaptured by existing experimental models. In this review, we argue that better human in vitro models, when critically assessed and integrated with omics data from human disease, can help bridge this gap. We examine how different in vitro systems, from simple monocultures to advanced co-culture and 3D platforms, can model human SMC plasticity, and how benchmarking against human single-cell and multi-omics data can guide model selection, validation, and refinement.