Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells

Abstract

The ability to generate visceral sensory neurons (VSN) from induced pluripotent stem (iPS) cells may help to gain insights into how the gut–nerve–brain axis is involved in neurological disorders. We established a protocol to differentiate human iPS-cell-derived visceral sensory ganglion organoids (VSGOs). VSGOs exhibit canonical VSN markers, and single-cell RNA sequencing revealed heterogenous molecular signatures and developmental trajectories of VSGOs aligned with native VSN. We integrated VSGOs with human colon organoids on a microfluidic device and applied this axis-on-a-chip model to Alzheimer’s disease. Our results suggest that VSN could be a potential mediator for propagating gut-derived amyloid and tau to the brain in an APOE4- and LRP1-dependent manner. Furthermore, our approach was extended to include patient-derived iPS cells, which demonstrated a strong correlation with clinical data. A protocol for differentiating visceral sensory ganglion organoids from induced pluripotent stem cells allows the establishment of an in vitro model for the gut–visceral nerve–brain axis and study of the propagation of pathogenic proteins involved in Alzheimer’s disease along the vagus nerve.