Human gastroids to model regional patterning in early stomach development.

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Gastroenterology

Background:

• The human stomach exhibits regional functional differences along its anterior-posterior axis.
• Animal models have historically informed stomach patterning studies.
• Human pluripotent stem (hPS)-cell-based gastric organoids are emerging but struggle to model early fundic-antral patterning.

Purpose of the Study:

• To develop a self-organized human gastric organoid model (gastroids) for studying fundic-antral patterning in vitro.
• To investigate the cellular and molecular mechanisms underlying gastric patterning during early organogenesis.

Main Methods:

• Generation of self-organized multilineage gastric organoids (gastroids) from hPS cells.
• Co-development involving multiple germ layers to mimic in vivo development.
• Single-cell transcriptomic profiling and genetic silencing to identify key signaling pathways and genes.

Main Results:

• Gastroids exhibit bipolar fundic-antral epithelial patterning, neural populations, and mesenchymal cells, mirroring in vivo stomach development.
• Non-endodermal cells, particularly neural populations, act as signaling centers instructing patterning via WNT-mediated crosstalk.
• NR2F2 was identified as a crucial mediator of fundic-antral patterning in gastroid development.

Conclusions:

• Human gastroids provide a high-fidelity in vitro model for studying gastric fundic-antral patterning.
• This study elucidates a principle for instructing gastric patterning, involving neural signaling and the NR2F2 gene.
• The findings advance the understanding of stomach organogenesis and the development of gastric organoids.