Signalling codes for the maintenance and lineage commitment of embryonic gastric epithelial progenitors

Abstract

The identity of embryonic gastric epithelial progenitors is unknown. We used single-cell RNA-sequencing, genetic lineage tracing and organoid assays to assess whether <i>Axin2</i>- and <i>Lgr5</i>-expressing cells are gastric progenitors in the developing mouse stomach. We show that <i>Axin2</i>⁺ cells represent a transient population of embryonic epithelial cells in the forestomach. <i>Lgr5</i>⁺ cells generate both glandular corpus and squamous forestomach organoids <i>ex vivo</i> Only <i>Lgr5</i>⁺ progenitors give rise to zymogenic cells in culture. Modulating the activity of the WNT, BMP and Notch pathways <i>in vivo</i> and <i>ex vivo</i>, we found that WNTs are essential for the maintenance of <i>Lgr5</i>⁺ epithelial cells. Notch prevents differentiation of the embryonic epithelial cells along all secretory lineages and hence ensures their maintenance. Whereas WNTs promote differentiation of the embryonic progenitors along the zymogenic cell lineage, BMPs enhance their differentiation along the parietal lineage. In contrast, WNTs and BMPs are required to suppress differentiation of embryonic gastric epithelium along the pit cell lineage. Thus, coordinated action of the WNT, BMP and Notch pathways controls cell fate determination in the embryonic gastric epithelium.