Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
117
Journal Issue
12
Pages
6717-6725
Date Issued
2020
Author(s)
Ho T.-C.
Wang E.-Y.
Horng J.-H.
Wu L.-L.
Chen Y.-T.
Huang H.-C.
Abstract
Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin-depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis. ? 2020 National Academy of Sciences. All rights reserved.
SDGs
Other Subjects
beta catenin; complement component C1q; beta catenin; complement component C1q; CTNNB1 protein, mouse; aged; animal cell; animal experiment; animal model; Article; cell dedifferentiation; cell differentiation; chronic hepatitis; controlled study; hepatic progenitor cell; human; human tissue; liver carcinogenesis; liver cell; liver tumor; macrophage; mouse; nonhuman; priority journal; senescence; stem cell expansion; animal; C57BL mouse; carcinogenesis; cell aging; chronic hepatitis; complication; immunology; knockout mouse; liver; liver cell carcinoma; liver tumor; male; metabolism; pathology; physiology; signal transduction; stem cell; transgenic mouse; tumor microenvironment; Animals; beta Catenin; Carcinogenesis; Carcinoma, Hepatocellular; Cell Differentiation; Cellular Senescence; Complement C1q; Hepatitis, Chronic; Humans; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Signal Transduction; Stem Cells; Tumor Microenvironment
Publisher
National Academy of Sciences
Type
journal article