Anatomical and functional maturation of the mid-gestation human enteric nervous system

Abstract

Immature gastrointestinal motility impedes preterm infant survival. The enteric nervous system controls gastrointestinal motility, yet it is unknown when the human enteric nervous system matures enough to carry out vital functions. Here we demonstrate that the second trimester human fetal enteric nervous system takes on a striped organization akin to the embryonic mouse. Further, we perform ex vivo functional assays of human fetal tissue and find that human fetal gastrointestinal motility matures in a similar progression to embryonic mouse gastrointestinal motility. Together, this provides critical knowledge, which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance gastrointestinal motility in prematurity.

Enteric Nervous System Striped Patterning and Disease: Unexplored Pathophysiology

“…Recent studies have found that these ganglia are arranged in a series of circumferential stripes, which exhibit differences in thickness and spacing between intestinal regions. 5 , 6 Enteric neuronal stripes arise from reorganization of randomly distributed enteric neurons into an ordered pattern, and this gradual patterning occurs in both mouse embryos and human fetuses. 5 , 6 , 7 Similar reorganization occurs in chick embryos, although the resulting structure is a honeycomb.…”

“… 5 , 6 Enteric neuronal stripes arise from reorganization of randomly distributed enteric neurons into an ordered pattern, and this gradual patterning occurs in both mouse embryos and human fetuses. 5 , 6 , 7 Similar reorganization occurs in chick embryos, although the resulting structure is a honeycomb. 7 Both discrete ganglia and neuronal stripes arise in the SI before the colon.…”

“… 7 Both discrete ganglia and neuronal stripes arise in the SI before the colon. 5 , 6 , 27 In Sox10::CreER T2 ; R26R-Confetti mice, lineage tracing of sparse enteric neuronal precursors have revealed that cells within an enteric ganglion tend to be clonally related. 28 These clonally related cells are more likely to demonstrate coordinated activity as compared with non-clonally related cells, suggesting that organization into enteric ganglia is functionally relevant.…”

“… 32 , 33 The migrating cells in the MP eventually condense into discrete neuronal stripes, which arise in the SI around 14 PCW and in the colon around 21 PCW. 6 Of note, the human ENS has an added level of complexity with myenteric neurons that occupy an additional distinct plane from the neuronal stripes. 6 When viewed in maximum intensity projection, the combination of neuronal stripes and the additional plane reveals a neuronal grid not present in mouse.…”

“…Recent studies have interrogated ENS patterning along the longitudinal axis and have found that the ENS is organized into circumferential stripes in both mouse and human. 5 , 6 , 7 Although two-thirds of American adults report suffering from GI distress, 8 the relationship between ENS organization and the pathophysiology of GI disease is poorly understood.…”