| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
Recent evidence has demonstrated that cancers can be viewed as an abnormal organ in which tumor growth is driven by a population of cancer stem cells (CSCs) . It is believed that CSCs shares some common points with normal stem cells, which one of the origins is from uncontrolled self-renewal of normal stem cells and results in the continuous expansion of cancer cells and tumor formation. There is evident that BMI1, a Polycomb group protein, is essential for the self-renewal of hematopoietic, neural, and CSCs. However, it remains unclear whether disruption of stem cell function directly contributes to cancer initiation. In the present study, we separated and isolated putative human hepatic stem cells with flow cytometry from human primary fetal liver cells. The results of characterizing the stem cell properties showed us that the putative stem cell fraction possessed high efficient clonal expansion, multi-potential differentiation capability and self-renewal potentials as well as liver tissue reconstitute capability by the means of single cell based clonal assay, semi-quantitative RT-PCR, immunohistochemistry and BrdU label retaining cell assay and in vivo transplantation. Furthermore, we transfected BMI1 gene into isolated human stem cells and found out that forced expression of BMI1 in stem cells promoted the self-renewal of hepatic stem cells to form double size single cell derived clonal colonies in vitro but there is no affection on the clonal colony formation rate(clonogenicity) contrast to both of MOCK and wild type. On the other hand, the tumorigenicity of BMI1 over-expression human hepatic stem cells was also confirmed by transplantation into nonobese diabetic/severe combined immunodeficient mice. In a conclusion, abnormal regulation of self-renewal of human hepatic stem cells serves as an early event in hepatocacinogensis, and they highlight the important roles of BMI1 gene in regulating the self-renewal of normal or cancer stem cells in livers.
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