Survival of Stem Cells and Progenitors in the Intestine Is Regulated by LPA(5)-Dependent Signaling

BACKGROUND & AIMS: Regeneration of the epithelium by stem cells in the intestine is supported by intrinsic and extrinsic factors. Lysophosphatidic acid (LPA), a bioactive lipid mediator, regulates many cellular functions, including cell proliferation, survival, and cytokine secretion. Here, we identify LPA(5) receptor as a potent regulator of the survival of stem cells and transit-amplifying cells in the intestine. METHODS: We have used genetic mouse models of conditional deletion of Lpar5, Lpar5(f/f);Rosa-Cre(ERT) (Lpar5(KO)), and intestinal epithelial cell–specific Lpar5(f/f);AhCre (Lpar5(IECKO)) mice. Mice were treated with tamoxifen or β-naphthoflavone to delete Lpar5 expression. Enteroids derived from these mice were used to determine the effect of Lpar5 loss on the apoptosis and proliferation of crypt epithelial cells. RESULTS: Conditional loss of Lpar5 induced ablation of the intestinal mucosa, which increased morbidity of Lpar5(KO) mice. Epithelial regeneration was compromised with increased apoptosis and decreased proliferation of crypt epithelial cells by Lpar5 loss. Interestingly, intestinal epithelial cell–specific Lpar5 loss did not cause similar phenotypic defects in vivo. Lpar5 loss reduced intestinal stem cell marker gene expression and reduced lineage tracing from Lgr5(+) ISCs. Lpar5 loss induced CXCL10 expression which exerts cytotoxic effects on intestinal stem cells and progenitors in the intestinal crypts. By co-culturing Lpar5(KO) enteroids with wild-type or Lpar5(KO) splenocytes, we demonstrated that lymphocytes protect the intestinal crypts via a LPA(5)-dependent suppression of CXCL10. CONCLUSIONS: LPA(5) is essential for the regeneration of intestinal epithelium. Our findings reveal a new finding that LPA(5) regulates survival of stem cells and transit-amplifying cells in the intestine.