GITRL impairs hepatocyte repopulation by liver progenitor cells to aggravate inflammation and fibrosis by GITR+CD8+ T lymphocytes in CDE Mice

• Published in: Cell death & disease Vol. 15; no. 2; p. 114
• Main Authors: Li, Li, He, Yu, Liu, Kai, Liu, Lin, Shan, Shan, Liu, Helin, Ren, Jiangbo, Sun, Shujie, Wang, Min, Jia, Jidong, Wang, Ping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.02.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/106; 13/31; 13/51; 14/34; 38/77; 38/90; 38/91; 692/308/2171; 692/420/256/2515; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; CD8 antigen; CD8-Positive T-Lymphocytes - pathology; Cell Biology; Cell Culture; Cell differentiation; Cell lineage; Cell proliferation; Down-regulation; Ethionine; Fibrosis; Glucocorticoids; Glucocorticoids - metabolism; Hepatocytes; Hepatocytes - metabolism; Immunology; Inflammation - pathology; Life Sciences; Liver; Liver - pathology; Liver diseases; Lymphocytes; Lymphocytes T; Mice; Nutrient deficiency; Organoids; Progenitor cells; Receptors, Tumor Necrosis Factor - metabolism; Sox9 protein; Stem Cells - metabolism; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor Necrosis Factors - metabolism; Tumors; Wnt protein; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06506-y

As an alternative pathway for liver regeneration, liver progenitor cells and their derived ductular reaction cells increase during the progression of many chronic liver diseases. However, the mechanism underlying their hepatocyte repopulation after liver injury remains unknown. Here, we conducted progenitor cell lineage tracing in mice and found that fewer than 2% of hepatocytes were derived from liver progenitor cells after 9 weeks of injury with a choline-deficient diet supplemented with ethionine (CDE), and this percentage increased approximately three-fold after 3 weeks of recovery. We also found that the proportion of liver progenitor cells double positive for the ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL, also called Tnfsf18) and SRY-related HMG box transcription 9 (Sox9) among nonparenchymal cells increased time-dependently upon CDE injury and reduced after recovery. When GITRL was conditionally knocked out from hepatic progenitor cells, its expression in nonparenchymal cells was downregulated by approximately fifty percent, and hepatocyte repopulation increased by approximately three folds. Simultaneously, conditional knockout of GITRL reduced the proportion of liver-infiltrating CD8 + T lymphocytes and glucocorticoid-induced tumour necrosis factor receptor (GITR)-positive CD8 + T lymphocytes. Mechanistically, GITRL stimulated cell proliferation but suppressed the differentiation of liver progenitor organoids into hepatocytes, and CD8 + T cells further reduced their hepatocyte differentiation by downregulating the Wnt/β-catenin pathway. Therefore, GITRL expressed by liver progenitor cells impairs hepatocyte differentiation, thus hindering progenitor cell-mediated liver regeneration.