The research in our lab aims to understand the molecular and cellular mechanisms that maintain the liver during health and disease. Our long-term research goals are to improve the understanding of liver disease pathophysiology, including liver cancer, and develop novel methods of liver therapy.
Hepatocytes are the primary cell type in the liver, responsible for the majority of the liver’s synthetic, metabolic and detoxification functions. A fundamental question in liver biology is where new hepatocytes arise in the liver. We recently identified a unique subpopulation of hepatocytes that function as hepatocyte stem cells and are responsible for maintaining hepatocyte turnover during homeostasis (Wang et al, Nature 2015).
Our findings suggest two novel concepts about hepatocytes and liver homeostasis. First, hepatocytes consist of at least two distinct cell types, a stem cell population and a more differentiated hepatocyte population. This is in stark contrast to the traditional viewpoint that hepatocytes represent a single terminally differentiated cell type. Second, the hepatic lobule is maintained during homeostasis by a locally restricted stem cell population which gives rise to cells that differentiate and mature as they migrate away from the stem cell niche. This model of stem cell organization is reminiscent of that found in the intestinal crypt and skin epidermis. The ongoing research in our lab will expand on these two concepts.
1. Understanding the biology of hepatocyte stem cells: We are interested in examining the role of adult hepatocyte stem cells in mouse and human liver in the context of development, injury and cancer. Some questions we are addressing are:
- Do adult hepatocyte stem cells exist in the normal human liver?
- What is the role of hepatocyte stem cells in liver regeneration after different forms of liver injury?
- What is the developmental origin of adult hepatocyte stem cells?
- Are adult hepatocyte stem cells a potential liver cancer initiation cell?
2. Generating a liver cell atlas: A major goal of the lab is to identify and characterize distinct hepatocyte sub-populations with the aim of generating a single cell resolution map of the liver lobule. Some questions we are addressing are:
- Are there functionally distinct types of hepatocytes?
- What are the molecular signals responsible for patterning hepatocyte across the liver lobule?
- What is the role of non-parenchymal cells in patterning the liver lobule?
- Do different liver diseases preferentially affect distinct hepatocyte subtypes?