Distinct Phospholipase C-β Isozymes Mediate Lysophosphatidic Acid Receptor 1 Effects on Intestinal Epithelial Homeostasis and Wound Closure

Abstract

Maintenance of the epithelial barrier in the intestinal tract is necessary to protect the host from the hostile luminal environment. Phospholipase C-␤ (PLC-␤) has been implicated to control myriad signaling cascades. However, the biological effects of selective PLC-␤ isozymes are poorly understood. We describe novel findings that lysophosphatidic acid (LPA) regulates PLC-␤1 and PLC-␤2 via two distinct pathways to enhance intestinal epithelial cell (IEC) proliferation and migration that facilitate wound closure and recovery of the intestinal epithelial barrier. LPA acting on the LPA 1 receptor promotes IEC migration by facilitating the interaction of G␣q with PLC-␤2. LPA-induced cell proliferation is PLC-␤1 dependent and involves translocation of G␣q to the nucleus, where it interacts with PLC-␤1 to induce cell cycle progression. An in vivo study using LPA 1 -deficient mice (Lpar1 ؊/؊ ) shows a decreased number of proliferating IECs and migration along the crypt-luminal axis. Additionally, LPA enhances migration and proliferation of IECs in an LPA 1 -dependent manner, and Lpar1 ؊/؊ mice display defective mucosal wound repair that requires cell proliferation and migration. These findings delineate novel LPA 1 -dependent lipid signaling that facilitates mucosal wound repair via spatial targeting of distinct PLC-␤s within the cell.

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…Despite these data, some controversy exists as to whether LPA and ATX are truly angiogenic, although both appear to help in vessel maintenance. Interestingly, increased LPA levels can rapidly and reversibly increase blood brain barrier permeability (80), suggesting a concentration-dependent mechanism. Finally, LPA can also regulate vascular tone, such as posthemorrhagic vasoconstriction in cerebral microvasculature (81) or vasodilation in the thoracic aorta (82).…”

“…LPA 1 antagonists are also being tested clinically for disease amelioration: SAR-100842 for systemic sclerosis and AM-152 for idiopathic pulmonary fi brosis (200). Exogenous LPA exposure can also increase blood brain barrier permeability, which may be relevant to diseases and drug delivery into the brain (80). In the next section, LPA-mediated pathophysiologies across organ systems will be discussed, with specifi c mention of LPA signaling modulators in therapeutic contexts (Table 2).…”

Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis

“…To initiate injury, forceps physically remove a small fragment of the distal colon mucosa, while leaving the underlying muscularis propria intact. A major strength of this experimental system is that it is amenable to quantitative analysis of in vivo lesions due to the precise timing and location of mucosal damage and repair (8)(9)(10)(11)(12)(13). Thus, the in vivo mechanisms of mucosal repair are tractable using this model.…”

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells

“…2 (2)(3)(4)(5)(6). Despite their fundamental importance for understanding intestinal homeostasis, wound healing, and pathogenesis of human diseases, the intracellular signal transduction mechanisms that mediate GPCRinduced proliferation of intestinal epithelial cells remain incompletely understood.…”