Single-cell profiling coupled with lineage analysis reveals vagal and sacral neural crest contributions to the developing enteric nervous system

Abstract

During development, much of the enteric nervous system (ENS) arises from the vagal neural crest that emerges from the caudal hindbrain and colonizes the entire gastrointestinal tract. However, a second ENS contribution comes from the sacral neural crest that arises in the caudal neural tube and populates the post-umbilical gut. By coupling single cell transcriptomics with axial-level specific lineage tracing in avian embryos, we compared the contributions of embryonic vagal and sacral neural crest cells to the chick ENS and the associated peripheral ganglia (Nerve of Remak and pelvic plexuses). At embryonic day (E) 10, the two neural crest populations form overlapping subsets of neuronal and glia cell types. Surprisingly, the post-umbilical vagal neural crest much more closely resembles the sacral neural crest than the pre-umbilical vagal neural crest. However, some differences in cluster types were noted between vagal and sacral derived cells. Notably, RNA trajectory analysis suggests that the vagal neural crest maintains a neuronal/glial progenitor pool whereas this cluster is depleted in the E10 sacral neural crest which instead has numerous enteric glia. The present findings reveal sacral neural crest contributions to the hindgut and associated peripheral ganglia and highlight the potential influence of the local environment and/or developmental timing in differentiation of neural crest-derived cells in the developing ENS.

Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue

“…9 10 These NC cells predominantly migrate from the neural tube at the vagal axial level to acquire ENS progenitor features while colonising the GI tract, giving rise to enteric neurons and glia, [11][12][13] with a smaller contribution arising from the sacral NC or via Schwann cell precursors. [14][15][16][17] In HSCR, ENS progenitors fail to migrate, proliferate or differentiate along variable lengths of the distal gut, which remain aganglionic and fail to function. 18 The underlying mechanisms for this failure remain unclear and are likely multifactorial, although disruption of the RET signalling pathway seems to play a key role in a significant number of cases.…”