Biliary tract system is important for homeostasis of bile acid synthesis and transport. Intrahepatic bile ducts are consist of cholangiocytes derived from hepatic stem/progenitor cells. In the early stage of liver development, foregut endoderm, stimulated by cytokines derived from heart and septum transversum, differentiates into the liver bud, the early-liver organ. In the liver bud, hepatoblasts, hepatic stem/progenitor cells in the fetal livers, proliferate and differentiate into both hepatocytes and cholangiocytes. Intrahepatic bile-duct injury causes hepatic cell death and severe liver diseases. There are few system to analyze development and fucntions of human bile ducts. In this project, we will establish a new in vitro and in vivo system for analyses of human biliary system.

We recently established purification and culture methods of hepatoblast-like cells derived from human iPS cells. Human iPS cells are stimulated by several cytokines and hepatoblast cell surface markers-positive cells are co-cultured with feeder cells. These cells can differentiate into alpha feto-protein positive hepatocytic cells and proliferate for a long time.
For the purpose to analyses human biliary system, we will develop methods for differentiation of iPS-drived hepatoblasts into intrahepatic bile ductal cells. In addition, we will develop an in vivo expansion system for human biliary cells using cholangiocyte-deficient mouse model.

There are several diseases which are caused by the dysfunction of biliary tract system. However, the molecular mechanism of human bile duct diseases remains unknown. Human iPS cells can be established from these patients and we have a plan to analyze these diseases using bile ductal cells derived from patient-specific hiPS cells. Our future findings in this project will contribute to develop new therapies for these biliary diseases.