Compensatory Upregulation of LPA2 and Activation of the PI3K-Akt Pathway Prevent LPA5-Dependent Loss of Intestinal Epithelial Cells in Intestinal Organoids

Renewal of the intestinal epithelium is orchestrated by regenerative epithelial proliferation within crypts. Recent studies have shown that lysophosphatidic acid (LPA) can maintain intestinal epithelial renewal in vitro and conditional deletion of LPAR5 (LPAR5^iKO) in mice ablates the intestinal epithelium and increases morbidity. In contrast, constitutive LPAR5 deletion (LPAR5^cKO) does not cause a defect in intestinal crypt regeneration. In this study, we investigated whether another LPA receptor (LPAR) compensates for constitutive loss of LPA₅ function to allow regeneration of intestinal epithelium. In LPAR5^cKO intestinal epithelial cells (IECs), LPAR2 was upregulated and blocking LPA₂ function reduced proliferation and increased Apoptosis of LPAR5^cKO IECs. Similar to LPAR5^cKO mice, the absence of LPAR2 (LPAR2^-/-) resulted in upregulation of LPAR5 in IECs, indicating that LPA₂ and LPA₅ reciprocally compensate for the loss of each other. Blocking LPA₂ in LPAR5^cKO enteroids reduced phosphorylation of Akt, indicating that LPA₂ maintains the growth of LPAR5^cKO enteroids through activation of the PI3K-Akt pathway. The present study provides evidence that loss of an LPAR can be compensated by another LPAR. This ability to compensate needs to be considered in studies aimed to define receptor functions or test the efficacy of a LPAR-targeting drug using genetically engineered animal models.

LPA5; epithelial cells; intestine; lysophosphatidic acid; organoid.