LPA5-Dependent signaling regulates regeneration of the intestinal epithelium following irradiation

Abstract

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 LPA₅ 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 LPA₅ 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 LPA₅ 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 LPA₅ 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 (LPA₅) in intestinal epithelial cells and intestinal organoids to show that the LPA₅ receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA₅ induces YAP signaling and regulates Paneth cells.

Keywords: LPA; intestine; irradiation; regeneration; survival.