Conversion of Terminally Differentiated Cells to Progenitor Cells-A Trial of Tissue Regeneration Not by Targeting Stem Cells

终末分化细胞向祖细胞的转化——非靶向干细胞的组织再生试验

• 批准号: 21659454
• 负责人: IKEDA Masaaki
• 金额: $ 2.2万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21659454/
• 关键词: 再生歯学; iPS細胞; 最終分化細胞; エピジェネティック; 核マトリクス結合因子; 核内高次構造; 細胞増殖; 前駆細胞; クロマチン; 再生歯学; iPS細胞; 最終分化細胞; エピジェネティック; 核マトリクス結合因子; 核内高次構造; 細胞増殖; 前駆細胞; クロマチン

The pathways regulated by p53 and RB tumor suppressors play important roles in differentiation and irreversible cell-cycle arrest in terminally differentiated cells. To induce dedifferentiation and proliferation of terminally differentiated cells, we investigated functional roles of DRIL1 and its closely related DRIL2, family members of ARID(AT-rich interaction domain) DNA-binding proteins, in these major tumor suppressor pathways. We found that DRIL1 cooperates with p53 to activate pro-arrest p21^WAF1 transcription, and that DRIL1 and DRIL2 play important roles in E2F-target gene expression and cell cycle progression, and that DRIL2 function is required for osteogenic differentiation. In addition, our results suggest that, in addition to DRIL1 or DRIL2 knockdown, inhibition of p53 and RB functions is required for inducing dedifferentiation and proliferation of terminally differentiated cells. These results provide important insights to the conversion of terminally differentiated cells into progenitor cells.

由p53和RB肿瘤调节的途径在分化和不可逆的细胞周期停滞中在末端分化的细胞中起着重要作用。为了诱导终末分化细胞的去分化和增殖，我们研究了DRIL1及其密切相关的DRIL2的功能作用，即在这些主要肿瘤抑制途径中的ARID（富含相互作用结构域）DNA结合蛋白的家族成员。我们发现DRIL1与p53合作激活Pro-Trast P21^WAF1转录，并且Dril1和Dril2在E2F靶向基因的表达和细胞周期进程中起重要作用，而成骨分化需要DRIL2功能。此外，我们的结果表明，除了DRIL1或DRIL2敲低外，还需要抑制p53和RB功能来诱导末端分化细胞的去分化和增殖。这些结果为终末分化细胞转化为祖细胞提供了重要的见解。