# Unraveling enteroendocrine cell lineage dynamics and associated gene regulatory networks during intestinal development

## TL;DR

The study reveals how enteroendocrine cells develop in the gut, showing they follow similar paths as in adults, independent of diet or gut structures.

## Contribution

The study identifies gene regulatory networks controlling enteroendocrine cell differentiation during development using human intestinal organoids.

## Key findings

- EEC subtypes are specified during development through adult-like differentiation trajectories.
- EEC specification occurs independently of crypt-villus structures, diet, or microbiota.
- Some EEC subtypes depend on tissue maturation for their emergence.

## Abstract

Enteroendocrine cells (EECs) are rare intestinal epithelial cells producing multiple hormones that regulate essential aspects of digestion and energy. EEC subtypes, their hormone repertoire and differentiation mechanisms from intestinal stem cells have been characterized in the adult intestine. Although EECs must be functional from birth because their absence leads to severe intestinal malabsorption in newborns, the processes that determine their subtype specification during development remain largely unknown. We used mouse embryos, human pluripotent stem cell-derived intestinal organoid models and single-cell transcriptomics to characterize EEC lineages and dynamics during development. Our findings demonstrate that in both mice and humans, the majority of EECs are specified during development through similar differentiation trajectories to those observed in the adult intestine. This suggests that EEC subtype specification occurs independently of fully organized crypt-villus structures and stimulation by diet or microbiota. However, the emergence of certain EEC subtypes depends on tissue maturation. Finally, our integrative approach infers lineage-specific regulators dynamically, identifying new candidates controlling EEC differentiation in the developing human gut.

Summary: The study reveals that during development, enteroendocrine cells follow adult-like differentiation trajectories, independently of crypt-villus structure, diet, or microbiota, and identifies gene regulatory networks driving their diversification in human stem cell-derived intestinal organoids.