Activation of the EGFR-PI3K-CaM Pathway by PRL-1 Ameliorates Liver Cirrhosis via ER Stress-dependent Calcium

Abstract

Background: Accumulation of cholesterol and depletion of calcium induce hepatic injury through the endoplasmic reticulum (ER) stress response. ER stress regulates the calcium imbalance between the ER and mitochondria. Previously, we reported that phosphatase of regenerating liver-1 (PRL-1)-overexpressing placenta-derived mesenchymal stem cells (PD-MSCsPRL-1) promoted liver regeneration through mitochondrial dynamics in a cirrhotic rat model. However, whether PRL-1 is involved in ER stress-dependent calcium is unclear. So, we demonstrated that PD-MSCsPRL-1 improves hepatic functions by regulating ER stress and calcium channels in a rat model of bile duct ligation (BDL). Methods: Liver cirrhosis was induced in Sprague-Dawley (SD) rats using surgically induced BDL for 10 days. PD-MSCs and PD-MSCsPRL-1 (2x106 cells) were intravenously administered to animals, and their therapeutic effects were analyzed. WB-F344 cells exposed to thapsigargin (TG) were cocultured with PD-MSCs or PD-MSCsPRL-1. Results: ER stress markers (e.g., eIF2α, ATF4, and CHOP) were increased in the non-transplantation group (NTx) compared with the control group. PD-MSCsPRL-1 significantly decreased ER stress markers compared to NTx and induced dynamic changes in calcium channel markers (e.g., SERCA2b, IP3R, MCU, and VDAC1) (*p<0.05). In TG-treated WB-F344 cells, cocultivation with PD-MSCsPRL-1 decreased cytosolic CaM expression and cytosolic and mitochondrial Ca2+ concentrations; however, the ER Ca2+ concentration was increased compared to that in PD-MSCs (*p<0.05). Additionally, PRL-1 through epidermal growth factor receptor (EGFR) activated phosphatidylinositol-3-kinase (PI3K) signaling, resulting in calcium increases via CaM expression. Conclusions: These findings suggest that PD-MSCsPRL-1 improved hepatic functions through calcium changes and attenuated ER stress in a BDL-injured rat model. Therefore, these results provide useful data for the development of next-generation MSC-based stem cell therapy for regenerative medicine in chronic liver disease.