Bioengineering of Heart–Brain Codevelopoid Model Via Trans-Germ-Layer Codevelopment Organoid Chip

Interorgan interactions are essential for organogenesis and maturation, with their dysregulation leading to developmental disorders. However, the ability of current physiologically relevant human models to recapitulate interorgan crosstalk during early developmental stages remains limited. Here, we develop a trans-germ-layer codevelopment organoid chip (TGCO-Chip) that enables the coemergence of two interconnected distinct organoids from a common upstream-lineage stem cell aggregate under well-controlled biochemical conditions. Specifically, we established a human pluripotent stem cell-derived heart–brain codevelopoid (HBC) model using a TGCO-Chip, and the codevelopoid recapitulated the developmental features of the heart and brain, including cell lineages, tissue architecture, and functionality. Furthermore, codevelopoids emulate neural projections to cardiac tissues and their regulatory effects during the early developmental stage of organogenesis. Compared with the interconnected heart–heart organoids, the neural compartment significantly increased the average cardiac beating rates and contraction amplitudes. Transcriptomic analysis confirmed that neural compartments in HBCs promoted cardiac differentiation and maturation. Overall, the TGCO-Chip platform provides an innovative tool for bioengineering multiorganoid complexes derived from shared progenitor lineages. Codevelopoids hold immense potential for applications in developmental biology, disease modeling, and regenerative medicine and can provide unprecedented insights into the dynamic interactions between different cell lineages and tissues.