CTGF is an intercellular mediator to stimulate hepatic stellate cells and promote hepatic fibrosis. Young Award

Background and aims: Connective tissue growth factor (CTGF) is one of matricellular proteins. This study was aimed to clarify its source and pathophysiological roles in liver fibrogenesis.
Methods: Bile duct ligation (BDL) was performed to induce liver fibrosis in mice. Eighty-nine liver biopsy samples were obtained from 89 patients with HBV or HCV to evaluate hepatic CTGF expression. Surgically resected non-tumorous liver samples were obtained from 12 HCC patients for single-cell RNA-sequence. Cell line of hepatocytes (HepG2 and Ac2F), hepatic stellate cells (HSCs) (LX-2 and RI-T), and liver sinusoidal endothelial cells (LSECs) (TMNK-1) were used for culture.
Results: In BDL model mice, CTGF was up-regulated both in hepatocytes and non-parenchymal cells (NPCs). BDL-induced liver fibrosis was attenuated, when CTGF was knocked out both in hepatocytes and NPCs (MX1-Cre+ CTGF^flox/flox + poly IC). In biopsy samples, hepatic CTGF was up-regulated in patients with cirrhosis compared with non-cirrhotic patients. Single-cell RNA-sequence identified hepatocytes, HSCs, and LSECs as a source of CTGF in the fibrotic liver. In cell culture experiments, recombinant CTGF treatment induced activation and collagen production from HSCs via integrin-mediated NF-kB activation. When co-cultured with HSCs, both hepatocytes and LSECs promoted activation and collagen production from HSCs, via paracrine CTGF secretion. Conclusion: CTGF is produced from multiple cell types and act as an intercellular mediator to promote hepatic fibrosis.