Treating a Failing Liver
It is estimated that more than three million Canadians have chronic liver disease and the incidence of some forms is increasing dramatically. Although treatments exist for early stages of the disease, progression to liver failure requires transplantation of a new organ. As the demand for transplantation far exceeds the number of available donor organs, only a limited number of patients will receive this treatment. The regeneration and repair of damaged and diseased livers through transplantation of new liver cells made from human pluripotent stem cells (hPSCs) offers a potential new therapy to treat these patients.
Our Discoveries
- Developed methods to make liver progenitors (hepatoblasts) from hPSCs.
- Identified methods to generated functional liver cells (hepatocytes) and bile duct cells (cholangiocytes) from the hPSC-derived hepatoblasts.
- Demonstrated that hPSC-derived cholangiocytes can be used to study Cystic Fibrosis in the Petri dish and to identify new drugs to treat this disease.
Our Research
The McEwen Institute's liver regeneration program is directed by Dr. Shinichiro Ogawa. By translating knowledge of human liver development to the differentiation cultures, Dr. Ogawa has identified the regulatory pathways that promote the development of two of the main cell types in the liver —hepatocytes and cholangiocytes (bile duct cells) — from hPSCs. The cells generated under these conditions display many characteristics and properties of hepatocytes and cholangiocytes found in the adult organ. Based on these advances, it has been possible to establish differentiation protocols that promote the efficient development of both cell types in culture. With access to the hPSC-derived hepatocytes, we have begun transplantation experiments using laboratory models engineered to undergo liver failure as pre-clinical studies to determine if it is possible to restore liver function with this approach.
Our studies using hPSC-derived cholangiocytes are focused on developing models to study Cystic Fibrosis liver disease (CFLD), which impairs the function of bile ducts in the liver. Using this model, it is possible to establish high throughput screens to identify new drugs to treat CFLD. In addition to the hepatocytes and cholangiocytes, the liver contains a number of other cell types including immune cells, stellate cells and sinusoidal endothelial cells that play important roles in normal liver function and in liver disease. Given this, it will be important to be able to generate all of these cell types from hPSCs to develop cell-based therapies to treat a broad range of diseases.
Current projects include:
- Further specification and maturation of hepatocytes and cholangiocytes.
- Testing the regenerative potential of hPSC-derived hepatocytes in pre-clinical models of liver failure.
- Development of functional liver sinusoidal endothelial cells, stellate cells, and macrophages from hPSCs.
- Generation of engineered liver tissue using hPSC-derived liver cell types.
- Transplantation of engineered liver tissue into pre-clinical models of liver failure.
- Modelling liver disease in vitro using hPSC-derived liver cell types.
