R-spondin 3 governs secretory differentiation in the gastric oxyntic glands

Abstract

The gastric oxyntic glands are maintained by gastric stem cells that continuously supply all differentiated cell types within the corpus epithelium. Stem cells are supported by stromal cells that make up the stem cell niche. In this issue of the JCI, Fischer et al. report on their use of genetically engineered mouse models and organoids to study the role of R-spondin 3 (RSPO3) in the stomach. RSPO3, one of the major stem cell niche factors, primarily promoted secretory differentiation in the normal stomach, but also contributed to regeneration following injury. Mechanistically, RSPO3 was upregulated in the stroma by loss of chief cells and then activated the YAP pathway in gastric stem and progenitor cells, which appeared to be critical for regeneration of the secretory lineage. These data substantially advance our understanding of the regulation of gastric stem cells and highlight a function for RSPO3 in the gastrointestinal tract, which is as the gatekeeper of secretory differentiation.

Figure 1. RSPO3 modulates secretory differentiation in the oxyntic glands.

Stem cells residing at the corpus isthmus supply daughter cells bidirectionally. Surface pit cells are supplied upwards from the isthmus, while other cell types, including mucous neck, chief, and parietal cells, are supplied downwards. Under normal homeostasis, stromal myofibroblasts secrete RSPO3 and regulate cellular differentiation from isthmus stem cells, presumably via the Lgr4 receptor. Thus, RSPO3 overexpression leads to an increase in chief and parietal cells and a decrease in surface pit cells. Loss of chief cells, induced by acute mucosal injury or genetic ablation, triggers upregulation of RSPO3 in myofibroblasts. In the regenerative state, upregulated RSPO3 activates stem cells, induces their proliferation and expansion, and promotes secretory differentiation to restore the depleted cell lineages (i.e., chief and parietal cells).