From chemically defined hiPSCs to self-organizing cardiac organoids: current strategies guided by developmental...

Cardiovascular research and drug development remain constrained by the limited translational relevance of conventional animal and in vitro cellular models, which represent a major bottleneck in the field. In recent years, self-organizing cardiac organoids derived from hiPSCs have emerged as a promising alternative. These organoids recapitulate key aspects of human cardiac development, physiological function, and disease-related features in vitro, thereby providing a powerful platform for mechanistic studies and drug screening. The successful establishment of such systems relies on two critical components. First, chemically defined and xeno-free hiPSC culture systems are essential for ensuring experimental standardization and reproducibility. Second, a comprehensive understanding of key developmental signaling pathways (e.g., Wnt and BMP/Activin) and their precise spatiotemporal regulation is required to enhance the maturation and biomimetic fidelity of three-dimensional cardiac models. In this review, we summarize the progression from standardized hiPSC culture systems to the generation of self-organizing cardiac organoids, with a particular focus on the regulatory mechanisms and engineering strategies underlying core developmental signaling pathways. We further discuss the potential applications of this technology in precision cardiovascular medicine.