Activation of the EGFR-PI3K-CaM pathway by PRL-1-overexpressing placenta-derived mesenchymal stem cells ameliorates liver cirrhosis via ER stress-dependent calcium

Gi Jin Kim,Won Tae Jeong,Si Hyun Bae,Soo Young Park,Jin Man Kim,Se Ho Kim,Jae Yeon Kim

doi:10.1186/s13287-021-02616-y

Gi Jin Kim, Won Tae Jeong + Show 5 more

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https://doi.org/10.1186/s13287-021-02616-y

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Abstract

BackgroundCholesterol accumulation and calcium depletion induce hepatic injury via the endoplasmic reticulum (ER) stress response. ER stress regulates the calcium imbalance between the ER and mitochondria. We previously reported that phosphatase of regenerating liver-1 (PRL-1)-overexpressing placenta-derived mesenchymal stem cells (PD-MSCsPRL−1) promoted liver regeneration via mitochondrial dynamics in a cirrhotic rat model. However, the role of PRL-1 in ER stress-dependent calcium is not clear. Therefore, we demonstrated that PD-MSCsPRL−1 improved hepatic functions by regulating ER stress and calcium channels in a rat model of bile duct ligation (BDL).MethodsLiver cirrhosis was induced in Sprague–Dawley (SD) rats using surgically induced BDL for 10 days. PD-MSCs and PD-MSCsPRL−1 (2 × 106 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.ResultsER stress markers, e.g., eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were increased in the nontransplantation group (NTx) compared to the control group. PD-MSCsPRL−1 significantly decreased ER stress markers compared to NTx and induced dynamic changes in calcium channel markers, e.g., sarco/endoplasmic reticulum Ca2+ -ATPase 2b (SERCA2b), inositol 1,4,5-trisphosphate receptor (IP3R), mitochondrial calcium uniporter (MCU), and voltage-dependent anion channel 1 (VDAC1) (*p < 0.05). Cocultivation of TG-treated WB-F344 cells with PD-MSCsPRL−1 decreased cytosolic calmodulin (CaM) expression and cytosolic and mitochondrial Ca2+ concentrations. However, the ER Ca2+ concentration was increased compared to PD-MSCs (*p < 0.05). PRL-1 activated phosphatidylinositol-3-kinase (PI3K) signaling via epidermal growth factor receptor (EGFR), which resulted in calcium increase via CaM expression.ConclusionsThese findings suggest that PD-MSCsPRL−1 improved hepatic functions via 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.

Highlights

The endoplasmic reticulum (ER) is responsible for various cellular activities, such as protein secretion, synthesis, maturation, translation and folding in eukaryotic cells, and it plays an important role in regulating calcium concentrations [1]
PD‐MSCsPRL−1 decreased ER stress in a rat model of bile duct ligation (BDL) and hepatocytes PKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling in the unfolded protein response (UPR) pathway is implicated in liver diseases [23]
To analyze UPR pathway activation by PD-MSCPRL−1 transplantation, we assessed the expression of CHOP, which is an ER stress-mediated transcription factor, in liver tissues using immunohistochemistry (IHC) (Fig. 1a)

Summary

Introduction

The endoplasmic reticulum (ER) is responsible for various cellular activities, such as protein secretion, synthesis, maturation, translation and folding in eukaryotic cells, and it plays an important role in regulating calcium concentrations [1]. ER stress induces the accumulation of misfolded proteins or calcium depletion in the ER lumen, and these events result in progression to severe stages of several diseases, such as diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) [2]. The role of ER stress-dependent calcium influx in liver diseases, including cirrhosis, is not known. Cholesterol accumulation and calcium depletion induce hepatic injury via the endoplasmic reticulum (ER) stress response. We demonstrated that PD-MSCsPRL−1 improved hepatic functions by regulating ER stress and calcium channels in a rat model of bile duct ligation (BDL)

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