Progression of chronic liver disease to fibrosis, cirrhosis, and cancer is the common course of several liver diseases, but treatments for the end-stage liver disease are limited highlighting the critical need to identify a novel therapeutic target. Despite the numerous evidence indicating that accumulation of hepatic progenitor cells (HPCs) - the epithelial compartment of ductular reactions - is associated with fibrosis, definitive evidence supporting the causal role of HPCs in progression of fibrotic liver disease and cancer remains largely uncertain mainly due the lack of a mouse model that allows conditional labeling and tracing of HPCs. Furthermore, although increased angiogenesis in cirrhotic livers is a risk factor for tumorigenesis, whether and how HPCs signal to endothelial cells remains as a knowledge gap. We have previously reported that the forkhead box L1 (Foxl1)- Cre transgenic line can be used for specific labeling and isolation of HPCs. Using this new mouse model, we generated preliminary data indicating that inhibition of Notch signaling in HPCs leads to decreased angiogenesis and fibrosis in mice with chronic liver disease and increased differentiation of HPCs into cells with hepatocytic morphology. Our data also indicate that HPCs secrete several paracrine factors to stimulate proliferation of endothelial cells and angiogenic gene expression. This led to our central hypothesis that Foxl1+ HPCs promote progression of liver disease by crosstalking with endothelial cells and hepatic stellate cells in a paracrine manner, and modulation of the Notch signaling pathway is a valid strategy to promote differentiation of HPCs and inhibit pathogenic mechanisms. We propose HPCs as a novel and unique cellular target that can be modulated to simultaneously inhibit progression of fibrotic liver disease and tumorigenesis and promote liver regeneration. Our overall objective for the proposed study is to establish the causal role of HPCs in pathogenesis using experimental models that recapitulate progression of human fibrotic disease. We will test our hypothesis with the following specific aims:
Aim 1 will determine the role of the Notch signaling pathway in reprogramming of Foxl1+ HPCs into mature hepatocytes in vivo.
Aim 2 will determine the cellular and molecular mechanism by which Foxl1+ HPCs regulate disease progression.
Aim 3 will determine the requirement for Foxl1+ HPCs in multiple stages of tumorigenesis.
Chronic liver disease often progresses to fibrosis, cirrhosis, and cancer, but treatments for advanced liver disease are limited. We aim to identify a novel cellular compartment that can be modulated to inhibit progression of fibrotic liver disease and to promote regeneration. The proposed work will reveal a number of disease-related cellular and molecular targets and will serve as the basis for future translational strategies.
