Human tri-tissue organoids model neuromusculoskeletal development and disease [bulk RNA-Seq]

The development and function of the human body involves the crosstalk between the central nervous system (CNS) and its innervated peripheral targets. One such essential crosstalk involves the connections between neural, muscular, and skeletal tissues, which have not yet been modeled with human cells. Here, we generate three-dimensional, tri-tissue organoids from human pluripotent stem cells that contain spinal cord, muscular, and skeletal components. The three distinct lineages co-develop in each single organoid and differentiate in a spatially-organized manner. The neural, muscular, and skeletal regions undergo maturation and can establish functional connections during organoid development. Using this system, we find that skeletal support is essential for human skeletal muscles’ structural and functional development. We also show that proinflammatory stimulation in skeletal regions, which resembles the pathological trigger in arthritis-associated conditions, leads to skeletal tissue degeneration, notably, causes neuromuscular structure and function deterioration. We anticipate that our tri-tissue organoids will provide a valuable model for future studies of human neuromusculoskeletal crosstalk and disease.