Gastric Enteroendocrine cells (gEEC): Development, Homeostasis and Response to Sleeve-Gastrectomy

The stomach serves a role in digestion through exocrine and endocrine secretions. Little is known concerning development and homeostasis of gEECs: X, D, EC and ECL cells. Stem cell populations and cell type lineages in the stomach are not well defined, there is a shortage in genetic tools in stomach research, and gastric organoids from adult tissues don’t give rise to reliable gEECs. This gap is surprising since gEECs secrete hormones that control hunger, motility and digestion.

scRNAseq on human gastric biopsies showed that PTF1a, a key TF in the development and maintenance of the exocrine pancreas, is expressed in ECLs. IHC methods confirmed this finding and showed cytoplasmic localization of PTF1a in mature ECLs and nuclear localization in other cells, presumably gEEC progenitors. Lineage tracing using PTF1a-CreER mice demonstrated that PTF1a is expressed in the common elusive gEEC progenitor.

Sleeve-gastrectomy, a treatment for obesity, is associated with changes in endocrine secretion. scRNAseq and histological studies on human gastric biopsies revealed an increase in the proportions of ECLs, and a decrease in X and D populations following surgery. This change was associated with upregulation of PTF1a and its exocrine target genes in ECLs. We hypothesize that PTF1a plays a key role in these changes, and in the development and homeostasis of gEECs.

We aim to study the differentiation processes of gEECs in vivo using local viral infections in transgenic mice. We will isolate PTF1a+ cells to generate an organoid model for gEECs which will enable further mechanistic studies in vitro.