Role of Polycomb group proteins in the hepatic stem cell self-renewal

Abstract

Stem cell are defined as having robust self-renewal and multilineage differentiation potential. It is thought that the self-renewal capability of stem cells can be established when both of the gene clusters involved in maintaining the undifferentiated state and cell differentiation state are expressed neutrally.
 In present study, we first investigated the role of Polycomb group (PcG) genes in the hepatic stem/progenitor cells. As a result, we revealed that forced expression of Bmi1 promoted the self-renewal of hepatic stem/progenitor cells. The transplantation of Bmi1 introduced cells clonally expanded from single hepatic stem/progenitor cells produced the tumor, which exhibited the histologic features of combined hepatocellular and cholangiocarcinoma. These observations imply that Bmi1 act as a positive regulator of self-renewal capability in hepatic stem cells.
 Moreover, to investigate the role of PcG protein complex in self-renewal of the hepatic stem cells, we performed functional analyses of Ring1B that is essential for gene silencing by coupling with Bmi1 directly. When performed functional analysis of Ring1B in hepatic stem/progenitor cells derived from Ring1B-KO mouse with single cell-based colony assay, self-renewal capability of hepatic stem/progenitor was inhibited. Moreover, cyclin-dependent kinase inhibitor, ink4a and arf genes that were thought to be target genes of Bmi1, were depressed in Ring1B-KO cells.
 These results indicate that Bmi1 and Ring1B are critical factor to self-renewal of hepatic stem/progenitor cells in the developing murine liver by suppressing a negative cell cycle regulators including Ink4a/Arf.