Retinoic Acid Accelerates the Specification of Enteric Neural Progenitors from In-Vitro-Derived Neural Crest

The enteric nervous system (ENS) is derived primarily from the vagal neural crest, a migratory multipotent cell population emerging from the dorsal neural tube between somites 1 and 7. Defects in the development and function of the ENS cause a range of enteric neuropathies, including Hirschsprung disease. Little is known about the signals that specify early ENS progenitors, limiting progress in the generation of enteric neurons from human pluripotent stem cells (hPSCs) to provide tools for disease modeling and regenerative medicine for enteric neuropathies. We describe the efficient and accelerated generation of ENS progenitors from hPSCs, revealing that retinoic acid is critical for the acquisition of vagal axial identity and early ENS progenitor specification. These ENS progenitors generate enteric neurons in vitro and, following in vivo transplantation, achieved long-term colonization of the ENS in adult mice. Thus, hPSC-derived ENS progenitors may provide the basis for cell therapy for defects in the ENS. •Retinoic acid alters the axial identity of hPSC-derived neural crest cells•ENS progenitor markers are upregulated in response to RA•ENS progenitors are capable of generating enteric neurons in vitro•hPSC ENS progenitors colonize the ENS of mice following long-term transplantation In this article, Frith and colleagues show that retinoic acid (RA) signaling alters the axial identity of hPSC-derived neural crest cells in a time- and dose-dependent manner. They utilized this to derive enteric nervous system (ENS) progenitors from hSPCs, which can differentiate to enteric neurons in vitro and colonize the ENS of adult mice following long-term transplantation.