Liver fibrosis is a general pathological feature associated with chronic liver diseases. As a compensatory response, Liver progenitor cells are activated to proliferate and differentiate into hepatocytes and cholangiocytes, thereby maintaining liver homeostasis The Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been considered as one kind of tissue-resident stem cell marker in various tissues with high self-renewal capacities, such as small intestine, and hair follicles. LGR5 expression is very low or even undetectable in the healthy liver but may appear in response to injury to aid in liver regeneration. These LGR5+ stem cells can be expanded in vitro in so-called tissue-specific organoids providing disease and patient-specific models to study disease pathologies and therapeutic tests. While LGR5+ cells have been widely studied, the source of LGR5+ cells, as well as the potential mechanisms of LGR5+ cells expansion in liver, is still unknown. In Chapter 1, a general introduction of WNT/β-catenin pathway and RSPO-LGR4/5-ZNRF3/RNF43 module, as well as their roles in liver development, homeostasis, zonation and disease is presented. The research aims of each experimental chapter were also presented. In Chapter 2, a review was provided on the application of various types of stem cell-based liver organoids in studying liver diseases and developing therapeutic approaches. Chapters 3 to 6 focused on the proliferation of LGR5+ cells in different etiologies of human chronic liver disease. Liver tissue-derived LGR5+ organoids were utilized to study the molecular mechanisms that promote the LGR5+ cell expansion in fibrotic liver disease.