R-Spondin1 protects gastric stem cells and mitigates gastric GVHD in allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is the major obstacle to perform allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that intestinal stem cells (ISCs) are targeted in lower gastrointestinal GVHD. A leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) expressing gastric stem cells (GSCs) reside at the base of the gastric glands in mice. After experimental allo-HCT, Lgr5+ GSCs significantly decreased. Parietal cells, which underwent continuous renewal by GSCs, were injured in gastric GVHD, leading to failure of gastric acidification and aerobic bacterial overgrowth in the duodenum. Fate mapping analysis demonstrated that administration of R-Spondin1 (R-Spo1) that binds to Lgr5 for 6 days in naïve mice significantly increased proliferating epithelial cells derived from Lgr5+ GSCs. R-Spo1 administrated on days -3 to -1 and +1 to +3 of allo-HCT protected GSCs, leading to amelioration of gastric GVHD and restoration of gastric acidification, and suppressed aerobic bacterial overgrowth in the duodenum. In conclusion, Lgr5+ GSCs were targeted by gastric GVHD, resulted in disruption of the gastric homeostasis, while R-Spo1 protected Lgr5+ GSCs from GVHD and maintained homeostasis in the stomach.