Christopher R. Schlieve 1 , 2 , Kathryn L. Fowler 1 , Matthew Thornton 3 , Sha Huang 4 , 5 , 6 , Ibrahim Hajjali 1 , Xiaogang Hou 1 , Brendan Grubbs 3 , Jason R. Spence 4 , 5 , 6 , Tracy C. Grikscheit 1 , 2 , ∗
10 August 2017
Acquired or congenital disruption in enteric nervous system (ENS) development or function can lead to significant mechanical dysmotility. ENS restoration through cellular transplantation may provide a cure for enteric neuropathies. We have previously generated human pluripotent stem cell (hPSC)-derived tissue-engineered small intestine (TESI) from human intestinal organoids (HIOs). However, HIO-TESI fails to develop an ENS. The purpose of our study is to restore ENS components derived exclusively from hPSCs in HIO-TESI. hPSC-derived enteric neural crest cell (ENCC) supplementation of HIO-TESI establishes submucosal and myenteric ganglia, repopulates various subclasses of neurons, and restores neuroepithelial connections and neuron-dependent contractility and relaxation in ENCC-HIO-TESI. RNA sequencing identified differentially expressed genes involved in neurogenesis, gliogenesis, gastrointestinal tract development, and differentiated epithelial cell types when ENS elements are restored during in vivo development of HIO-TESI. Our findings validate an effective approach to restoring hPSC-derived ENS components in HIO-TESI and may implicate their potential for the treatment of enteric neuropathies.
ENCC implantation restores enteric glial and neural subpopulations in HIO-TESI
ENCC differentiate into diverse neuronal subtypes and synapse with luminal ECC
ENCC-HIO-TESI demonstrates neuron-dependent contractility and relaxation
Early in vivo ENCC implantation alters the developing HIO-TESI transcriptome
Human intestinal organoid and enteric neural crest cell co-culture restores enteric nervous system (ENS) function. Schlieve and colleagues developed an in vivo approach to establish ENS elements in tissue-engineered small intestine that demonstrates neuron-dependent functional integration. This method could be applied to other organ systems and represent a future cellular therapy for human enteric neuropathies.