Theentericnervoussystem(ENS)accomplishesabroadrangeofactivitiesthatrelyonaremarkably diversepopulationofneuronalandglialsubtypes.Lossofspecificcelltypes,suchasnitricoxide(NO) producing neurons (nitrergic neurons) leads to enteric neuropathies associated with dysmotility disordersincludingesophagealachalasia,gastroparesisandinfantilehypertrophicpyloricstenosis.The underlying pathophysiology of these disorders have remained largely unknown due to limitations of currently available cellular models. We have recently reported a new alternative approach for differentiation of ENS lineages from human pluripotent stem cells under fully defined conditions, providing a unique and reliable framework for ENS disease modeling and drug discovery. Taking advantageofhighcontentchemicalcompoundscreeningincombinationwithfatemapreconstruction guided by single cell transcriptomics, here we propose a new strategy for efficient derivation and prospective isolation of enteric nitrergic neurons. This system will provide a unique in vitro model for identificationofpharmacologicalregulatoroftheseneuronsanddissectionofcellularmechanismsthat underlieGIdysmotilty.Wewillfurtherevaluatethepotentialoftheseneuronsintransplantationstudies aimedattheultimatedevelopmentofcell-basedtreatmentofentericneuropathiesrelatedtotheloss ofnitrergicneurons.
Thecellularpathophysiologyofgastrointestinalmotilitydisordersareextremelycomplexandelusive. Damage or loss of enteric inhibitory motor neurons is responsible for a broad range of gut motility disorders. Here, taking advantage of human pluripotent stem cell differentiation, we propose to establish an innovative framework to establish a new cellular model for the study enteric inhibitory neuronsandanexperimentalpipelineforcellreplacementtherapyinGIdysmotility.
