In conclusion, we

demonstrate that the mesodermal STM gives rise to MC/SubMCs. Y 27632 Moreover, MC/SubMCs give rise to both HSCs and PMCs, including PFBs, SMCs, and FBs during liver morphogenesis. Further studies on the mechanisms underlying a transition from MC/SubMCs to HSCs and PMCs may lead to better understanding of cell fate regulation of HSCs and PFBs in both embryonic and adult livers. The authors thank Peng Li and Henry Sucov for providing MesP1Cre mice and Raul Lazaro, Kiki Ueno, and Bin Xie for technical assistance. Additional Supporting Information may be found in the online version of this article. “
“We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1−/− Delta-like protein (Dlk)+ hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed Roxadustat price impaired growth activity. In contrast, Ink4a/Arf−/− Dlk+ cells gave

rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk+ cells. Although Ink4a/Arf−/− Dlk+ cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf−/− Dlk+ cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five down-regulated genes as candidate downstream DOK2 targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk+ cells strongly suppressed colony propagation and tumor growth. Conclusion: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf

locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells. (Hepatology 2010) Polycomb group (PcG) proteins operate as the cellular memory machinery through epigenetic chromatin modifications and are indispensable to the maintenance of cellular identity.1, 2 In particular, Bmi1, a core molecule of polycomb repressive complex 1 (PRC1), plays an important role in the self-renewal of various stem cell systems, including hepatic stem cells.