Enteric Nervous System Effects on Human Intestinal Development. – SyNEDI

The neonatal period is critical to the development of the gastrointestinal (GI) tract and is being recognized as a possible origin of common diseases that emerge at birth or late in life. Evidences have identified the enteric nervous system (ENS) as a key regulator of GI functions. However, the link between the molecular and cellular effects of the ENS on intestinal growth and maturation during the neonatal period remains elusive. We generated a complex human intestine derived from pluripotent stem cells and reassembling the ENS features to test the hypothesis that human ENS regulates intestinal development, growth, and maturation. Precisely, we will define the ENS mechanisms underlying human intestinal organoid development into a fully laminated and functional mature intestine (Aim 1). We will determine the influence of intestinal luminal contents (nutrients and microbiota) on the ENS phenotype and its associated functions (Aim 2).

The current proposal consists of numerous innovations that include:
1) Cognitive innovation with the generation of a human small intestine with and without a human enteric nervous system that constitutes an approach that offers an understanding of human cellular functions and relationships with the intestinal environment that is faster and more cost effective than murine models;
2) Technical innovation with unlimited resources of intestinal tissue with higher order complexity derived from pluripotent stem cells. This application employs novel methods for generating human intestinal tissues from pluripotent stem cells. These published and proposed human organoid systems are highly innovative and represent significant advance in our ability to study human GI development, physiology and diseases. This application will bring another level of innovation to the GI organoid systems by tissue engineering in the enteric nervous system;
3) Clinical innovation with unlimited resources of human-disease specific intestinal tissue from induced pluripotent stem cells. Conceptually, the proposal provides novel methods to directly test the ENS’s effects upon the intestinal epithelial functions that will provide a better understanding required for therapeutic approaches to functional GI disorders. Therefore, novel pathways and targeting mechanisms will be uncovered.

This proposal will allow for unprecedented studies of the molecular basis of human ENS control of GI functions during intestinal development including secretion, digestion, barrier function and GI diseases and will be an ideal screening platform for therapeutics that regulate the ENS.