<br>COMP通过CD36-ERK/AKT信号通路激活胰腺星状细胞促进胰腺纤维化,Cellular Signalling

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COMP通过CD36-ERK/AKT信号通路激活胰腺星状细胞促进胰腺纤维化
Cellular Signalling ( IF 4.4 ) Pub Date : 2024-03-11 , DOI: 10.1016/j.cellsig.2024.111135
Yi Wang ₁ , Hai-Tao Li ₂ , Gang Liu ₂ , Chuan-Shen Jiang ₂ , Yan-Hong Ni ₁ , Jing-Hui Zeng ₃ , Xia Lin ₄ , Qing-Yun Wang ₅ , Da-Zhou Li ₂ , Wen Wang ₂ , Xiang-Peng Zeng ₂

Affiliation

胰腺纤维化是慢性胰腺炎（CP）最重要的病理特征之一，胰腺星状细胞（PSC）是纤维化的关键细胞。作为一种细胞外基质（ECM）糖蛋白，软骨寡聚基质蛋白（COMP）对于胶原蛋白组装和ECM稳定性至关重要，最近的研究表明COMP在皮肤、肺和肝脏中发挥促进纤维化的作用。然而，COMP 在 PSC 激活和胰腺纤维化中的作用仍不清楚。我们的目的是研究COMP在调节PSC促纤维化表型和胰腺纤维化中的作用和具体机制。采用ELISA法测定CP患者血清COMP。通过重复腹腔注射雨蛙素建立CP小鼠模型，并通过苏木精-伊红染色（H&E）和天狼星红染色评估胰腺纤维化情况。采用免疫组化染色检测小鼠胰腺组织中COMP及α-SMA、纤连蛋白等纤维化标志物的表达变化。 Cell Counting Kit-8、Wound Healing 和 Transwell 评估了人胰腺星状细胞 (HPSC) 的增殖和迁移。采用Western blotting、qRT-PCR和免疫荧光染色检测HPSCs中纤维化标志物、AKT和MAPK家族蛋白的表达。采用RNA-seq组学分析以及COMP、重组人COMP（rCOMP）、MEK抑制剂和PI3K抑制剂的小干扰RNA来研究COMP对HPSCs激活的作用和机制。 ELISA结果显示CP患者血清中COMP的表达显着升高。 H&E和天狼星红染色分析显示，CP模型组小鼠体内存在大量胶原沉积，纤维化组织中COMP、α-SMA、纤连蛋白和波形蛋白高表达。 TGF-β1 刺激 HPSC 的激活并增加 COMP 的表达。 COMP 的敲低抑制了 HPSC 的增殖和迁移。进一步，RNA-seq组学分析和体外验证实验表明，rCOMP能够显着促进HPSCs的增殖和活化，这可能是由于通过膜蛋白受体CD36促进ERK和AKT的磷酸化。 rCOMP 同时增加 HPSC 中 α-SMA、纤连蛋白和 I 型胶原蛋白的表达。总之，本研究表明COMP在CP纤维化组织中上调，并且COMP通过CD36-ERK/AKT信号通路诱导PSC的活化、增殖和迁移。 COMP 可能是治疗 CP 的潜在候选药物。干扰 PSC 上 COMP 的表达或 COMP 与 CD36 之间的通讯可能是治疗研究的下一个方向。

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COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways

Pancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. ELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. ELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-β1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. In conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

更新日期：2024-03-11

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