Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
Cells. 2023 Jan 13;12(2):302. doi: 10.3390/cells12020302.
Connective tissue growth factor (CTGF) is involved in the regulation of extracellular matrix (ECM) production. Elevated levels of CTGF can be found in plasma from patients with liver fibrosis and in experimental animal models of liver fibrosis, but the exact role of CTGF in, e.g., diet-induced human liver fibrosis is not entirely known. To address this question, we utilized a 3D human liver co-culture spheroid model composed of hepatocytes and non-parenchymal cells, in which fibrosis is induced by TGF-β1, CTGF or free fatty acids (FFA). Treatment of the spheroids with TGF-β1 or FFA increased COL1A1 deposition as well as the expression of TGF-β1 and CTGF. Recombinant CTGF, as well as angiotensin II, caused increased expression and/or production of CTGF, TGF-β1, COL1A1, LOX, and IL-6. In addition, silencing of CTGF reduced both TGF-β1- and FFA-induced COL1A1 deposition. Furthermore, we found that IL-6 induced CTGF, COL1A1 and TGF-β1 production, suggesting that IL-6 is a mediator in the pathway of CTGF-induced fibrosis. Taken together, our data indicate a specific role for CTGF and CTGF downstream signaling pathways for the development of liver inflammation and fibrosis in the human 3D liver spheroid model.
结缔组织生长因子 (CTGF) 参与细胞外基质 (ECM) 产生的调节。纤维化患者的血浆和肝纤维化实验动物模型中均可发现 CTGF 水平升高，但 CTGF 在饮食诱导的人类肝纤维化中的确切作用尚不完全清楚。为了解决这个问题，我们利用由肝细胞和非实质细胞组成的 3D 人肝共培养球体模型，其中 TGF-β1、CTGF 或游离脂肪酸 (FFA) 诱导纤维化。TGF-β1 或 FFA 处理球体增加 COL1A1 沉积以及 TGF-β1 和 CTGF 的表达。重组 CTGF 以及血管紧张素 II 引起 CTGF、TGF-β1、COL1A1、LOX 和 IL-6 的表达和/或产生增加。此外，CTGF 沉默减少了 TGF-β1 和 FFA 诱导的 COL1A1 沉积。此外，我们发现 IL-6 诱导 CTGF、COL1A1 和 TGF-β1 的产生，表明 IL-6 是 CTGF 诱导纤维化途径中的一种介质。总之，我们的数据表明 CTGF 及其 CTGF 下游信号通路在人类 3D 肝球体模型中对肝脏炎症和纤维化的发展具有特定作用。
