genetic abolishment of hepatocyte proliferation activates hepatic stem cells肝细胞增殖的基因取消激活肝干细胞.pdfVIP

Genetic Abolishment of Hepatocyte Proliferation Activates Hepatic Stem Cells 1 1 1 1,2 Yoko Endo , Mingjun Zhang , Sachie Yamaji , Yong Cang * 1 Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America, 2 Life Sciences Institute, Zhejiang University, Hangzhou, China Abstract Quiescent hepatic stem cells (HSCs) can be activated when hepatocyte proliferation is compromised. Chemical injury rodent models have been widely used to study the localization, biomarkers, and signaling pathways in HSCs, but these models usually exhibit severe promiscuous toxicity and fail to distinguish damaged and non-damaged cells. Our goal is to establish new animal models to overcome these limitations, thereby providing new insights into HSC biology and application. We generated mutant mice with constitutive or inducible deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiquitin ligase, in hepatocytes. We characterized the molecular mechanism underlying the compensatory activation and the properties of oval cells (OCs) by methods of mouse genetics, immuno-staining, cell transplantation and gene expression profiling. We show that deletion of DDB1 abolishes self-renewal capacity of mouse hepatocytes in vivo, leading to compensatory activation and proliferation of DDB1-expressing OCs. Partially restoring proliferation of DDB1-deficient hepatocytes by ablation of p21, a substrate of DDB1 E3 ligase, alleviates OC proliferation. Purified OCs express both hepatocyte and cholangiocyte markers, form colonies in vitro, and differentiate to hepatocytes after transplan