Abstract 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.
Yang et al. (Fri,) studied this question.