LPA(5)-Dependent signaling regulates regeneration of the intestinal epithelium following irradiation.

Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA(5) receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA(5) in regulating intestinal epithelial regeneration. Control mice (Lpar5(f/f)) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5(IECKO)) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5(IECKO) mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA(5) on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5(Cont) or Lgr5(ΔLpar5)). Irradiation of organoids resulted in fewer numbers of Lgr5(ΔLpar5) organoids retaining Lgr5+-derived progenitor cells compared with Lgr5(Cont) organoids. Finally, we observed that impaired regeneration in Lpar5(IECKO) mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA(5) in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA(5)) in intestinal epithelial cells and intestinal organoids to show that the LPA(5) receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA(5) induces YAP signaling and regulates Paneth cells.