PRL-1 过表达胎盘间充质干细胞通过 ER 应激依赖的钙激活 EGFR-PI3K-CaM 通路改善肝纤维化
Activation of the EGFR-PI3K-CaM pathway by PRL-1-overexpressing placenta-derived mesenchymal stem cells ameliorates liver cirrhosis via ER stress-dependent calcium.
机构信息
Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea.
Research Institute of Placenta Science, CHA University, Seongnam, 13488, Republic of Korea.
出版信息
Stem Cell Res Ther. 2021 Oct 24;12(1):551. doi: 10.1186/s13287-021-02616-y.
BACKGROUND
Cholesterol 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-MSCs) 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-MSCs improved 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-MSCs (2 × 10 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-MSCs.
RESULTS
ER 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-MSCs significantly decreased ER stress markers compared to NTx and induced dynamic changes in calcium channel markers, e.g., sarco/endoplasmic reticulum Ca -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-MSCs decreased cytosolic calmodulin (CaM) expression and cytosolic and mitochondrial Ca concentrations. However, the ER Ca 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.
CONCLUSIONS
These findings suggest that PD-MSCs 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.
背景
胆固醇积累和钙耗竭通过内质网（ER）应激反应诱导肝损伤。ER 应激调节 ER 和线粒体之间的钙失衡。我们之前报道过，过表达磷酸酶再生肝脏-1（PRL-1）的胎盘间充质干细胞（PD-MSCs）通过肝硬化大鼠模型中的线粒体动力学促进肝脏再生。然而，PRL-1 在 ER 应激依赖性钙中的作用尚不清楚。因此，我们证明 PD-MSCs 通过调节胆管结扎（BDL）大鼠模型中的 ER 应激和钙通道来改善肝功能。
方法
通过手术诱导 BDL 10 天在 Sprague-Dawley（SD）大鼠中诱导肝硬化。将 PD-MSCs 和 PD-MSCs（2×10 个细胞）静脉内给予动物，并分析其治疗效果。将暴露于他普西他汀（TG）的 WB-F344 细胞与 PD-MSCs 或 PD-MSCs 共培养。
结果
与对照组相比，未移植组（NTx）的 ER 应激标志物，如真核起始因子 2α（eIF2α）、激活转录因子 4（ATF4）和 C/EBP 同源蛋白（CHOP）增加。与 NTx 相比，PD-MSCs 显著降低 ER 应激标志物，并诱导钙通道标志物的动态变化，如肌浆/内质网 Ca -ATPase 2b（SERCA2b）、肌醇 1,4,5-三磷酸受体（IP3R）、线粒体钙单向转运体（MCU）和电压依赖性阴离子通道 1（VDAC1）（*p<0.05）。与 PD-MSCs 共培养的 TG 处理的 WB-F344 细胞降低了细胞质钙调蛋白（CaM）表达以及细胞质和线粒体 Ca 浓度。然而，与 PD-MSCs 相比，内质网 Ca 浓度增加（*p<0.05）。PRL-1 通过表皮生长因子受体（EGFR）激活磷脂酰肌醇-3-激酶（PI3K）信号，导致 CaM 表达增加从而导致钙增加。
结论
这些发现表明，PD-MSCs 通过钙变化改善 BDL 损伤大鼠模型中的肝功能，并减轻 ER 应激。因此，这些结果为开发用于慢性肝病再生医学的下一代基于 MSC 的干细胞治疗提供了有用的数据。
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