Prospero-related homeobox 1 and liver receptor homolog 1 coordinately regulate long-term proliferation of murine fetal hepatoblasts
Prospero-related homeobox 1 and liver receptor homolog 1 coordinately regulate long-term proliferation of murine fetal hepatoblasts
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DOI：
10.1002/hep.22303
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发表时间：
2008-07-01
期刊：
影响因子：
13.5
通讯作者：
Nakauchi, Hiromitsu
中科院分区：
文献类型：
--
作者：
Kamiya, Akihide;Kakinuma, Sei;Nakauchi, Hiromitsu
在胎肝发育的早期到晚期，双能成肝细胞增殖并分化为肝细胞和胆管细胞。与肝细胞相关的同源异型盒1基因（Prox 1）在肝细胞中表达，Prox 1的失活导致早期肝脏发育缺陷，特别是胎儿肝细胞的错误迁移。Prox 1与另一种肝细胞富集的转录因子肝受体同源物1（Lrh 1）结合，并抑制其转录活性。然而，Prox 1和Lrh 1调节胎儿肝细胞特性的分子机制仍然未知。我们研究了Prox 1和Lrh 1在早期肝脏发育中的作用。将胚胎第13天肝脏来源的CD 45（-）Ter 119（-）Dlk（+）细胞纯化为胎肝干/祖细胞，并在低密度培养条件下检测源自单细胞的集落形成。我们发现，使用逆转录病毒感染的Prox 1过表达诱导胚胎肝干/祖细胞的迁移和增殖。相反，Lrh 1的过表达抑制集落形成。Prox 1诱导胎儿肝干/祖细胞的长期增殖，其表现出高增殖活性和分化的双能性。Prox 1上调细胞周期蛋白D2、E1和E2的表达，而抑制cdk抑制剂p16（ink 4a）的表达。此外，Prox 1的过表达显著抑制了p16（ink 4a）的近端启动子活性。结论：这些结果表明，Prox 1和Lrh 1协调调节肝干/祖细胞的发育，Prox 1通过抑制p16（ink 4a）的启动子活性诱导胎肝细胞增殖。
During early to late-fetal liver development, bipotential hcpatoblasts proliferate and differentiate into hepatocytes and cholangiocytes. The prospero-related homeobox 1 gene (Prox1) is expressed in hepatoblasts, and the inactivation of Prox1 causes defective early liver development, in particular, faulty migration of fetal hepatoblasts. Prox1 binds to another hepatocyte-enriched transcription factor, liver receptor homolog 1 (Lrh1), and suppresses its transcriptional activity. However, the molecular mechanism by which Prox1 and Lrh1 regulate the characteristics of fetal hepatic cells remains unknown. We investigated the contribution of Prox1 and Lrh1 in early liver development. Embryonic day 13 liver-derived CD45(-)Ter119(-)Dlk(+) cells were purified as fetal hepatic stem/progenitor cells, and formation of colonies derived from single cells was detected under low-density culture conditions. We found that overexpression of Prox1 using retrovirus infection induced migration and proliferation of fetal hepatic stem/progenitor cells. In contrast, overexpression of Lrh1 suppressed colony formation. Prox1 induced the long-term proliferation of fetal hepatic stem/progenitor cells, which exhibited both high proliferative activity and bipotency for differentiation. Prox1 up-regulated expression of cyclins D2, E1, and E2, whereas it suppressed expression of p16(ink4a), the cdk inhibitor. In addition, overexpression of Prox1 significantly inhibited the proximal promoter activity of p16(ink4a). Conclusion: These results suggested that Prox1 and Lrh1 coordinately regulate development of hepatic stem/progenitor cells and that Prox1 induces fetal hepatocytic proliferation through the suppression of the promoter activity of p16(ink4a).