Title:
Liver stem/progenitor cells in fetal and adult liver

Atsushi Miyajima
Institute of Molecular and Cellular Biosciences, The University of Tokyo

Abstract:
The liver is a central organ for homeostasis and consists of parenchymal hepatocytes and various kinds of non-parenchymal cells. In order to characterize liver cells, we have developed a panel of monoclonal antibodies for sorting murine liver cells and also culture systems to characterize sorted cells.
Liver stem cells give rise to both hepatocytes and bile duct epithelial cells (BECs). Hepatoblasts emerging from the foregut endoderm at mid gestation are considered liver stem cells. We found that the early hepatoblasts are characterized by the expression of EpCAM and Dlk. Dlk+ cells sorted from fetal liver contain clonogenic cells capable of differentiating to both hepatocytes and BECs, indicating that they contain liver stem cells. Mesenchymal cells with p75NTR in the periportal region express Jagged-1 and contribute to differentiation of Notch2+ hepatoblasts to BECs. The vast majority of hepatoblasts become hepatocytes and PCLP1+ mesothelial cells covering the liver parenchyma stimulate proliferation of fetal hepatocytes by producing growth factors, resulting in preferential proliferation of hepatocytes underneath the mesothelium in fetal liver.
Adult liver has an extraordinary capacity to regenerate, and after 70% hepatectomy the liver recovers its original mass by replicating the remaining hepatocytes. This process does not require the activation of liver stem cells. However, in a certain type of liver injury models, liver stem/progenitor-like cells, known as oval cells in rodents, proliferate around the portal vein. Although oval cells are proliferating cells, they are considered transiently amplifying progenitors rather than stem cells because of their limited proliferation potential. EpCAM is expressed in bile ducts and clonogenic and bipotential cells are present in EpCAM+ cells in normal adult liver, suggesting that there are potential liver stem cells. Characterization of liver stem/progenitor cells will be presented.

References:
Onitsuka I. , Tanaka M., and Miyajima A. Characterization and functional analyses of hepatic mesothelial cells in mouse liver development. Gastroenterology 138, 1525-1536, 2010.

Okabe M., Tsukahara Y., Tanaka M., Suzuki K., Saito S., Kamiya Y., Tsujimura T., Nakamura K., and Miyajima A. Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse livers. Development 136, 1951-1960, 2009.

Tanaka M., Okabe M., Suzuki K., Kamiya Y., Tsukahara Y., Saito S., and Miyajima A. Mouse hepatoblasts at distinct developmental stages are characterized by expression of EpCAM and DLK1: drastic change of EpCAM expression during liver development. Mech. Dev . 126, 665-676, 2009.

Suzuki.K., Tanaka.M.,Watanabe.N., Saito.S., Nonaka.H., and Miyajima A . The p75 neurotrophin receptor marks precursors of hepatic stellate cells and portal fibroblasts in mouse fetal liver.Gastroenterology 135, 270-281, 2008 .