Graft-versus-host disease targets R-spondin3-producing lymphatic endothelial cells in the small intestine

Abstract

Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation. The gastrointestinal tract is a major target organ of GVHD, and disruption of the barrier function of the intestinal mucosa leads to an influx of danger signals derived from intestinal microbiota, which may further exaggerate GVHD. We have shown that the recombinant human R-spondin1 protects intestinal stem cells against GVHD, improves intestinal dysbiosis, and ameliorates GVHD. However, the endogenous R-spondin-producing cells in the small intestine remained to be studied in greater detail. This study clarified that R-spondin3 is the predominant R-spondin protein produced in the mouse small intestine. We also found that R-spondin3 is predominantly produced by lymphatic endothelial cells. Furthermore, we found that GVHD targets lymphatic endothelial cells in the small intestine, leading to decreased R-spondin3 production. GVHD-induced reduction of endogenous R-spondin3 could delay intestinal epithelial regeneration, possibly resulting in GVHD deterioration.