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Mechanism of differentiation of ductal cells to βcells.

导管细胞向β细胞分化的机制。

基本信息

批准号：
21790285
负责人：
INADA Akari
金额：
$ 2.83万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21790285/
关键词：
糖尿病 β細胞前駆細胞膵管分化

项目摘要

We further studied the mechanism of differentiation of ductal cells to β cells. Although Pdx-1 is mainly restricted to β cells in the adult pancreas to regulate several β-cell specific genes, the increased Pdx-1 protein level in the duct has been reported in human obesity and the rodent regeneration mode. This coincident of increased Pdx-1 protein level imply that the regeneration mode the pancreas recapitulates embryonic development and that neogenesis contributes to the increased islet mass. To test our hypothesis that Pdx-1 expression in the duct could be critical factor for the differentiation of ductal cells to β cells, we generated duct-specific Pdx-1 knockout mice by crossing the CAII-Cre mice to Pdx-1flE2/flE2 mice, in which Pdx-1 expression in the duct was knocked out around the birth. Inactivation of Pdx-1 in the duct resulted in reduced β cells in normal growth which caused hyperglycemia and glucose tolerance. Moreover, in the regeneration study new β-cell formation was rarely seen in the adult. Thus, the activation of Pdx-1 in the duct is required for differentiation, and these differentiated β cells contribute to intensive β-cell growth in neonatal period and injury in the adult. Our study provides clear evidence of a compensatory function of a ductal-origin β cell.These findings should encourage further exploration of pancreatic duct cells as a source for islet regeneration. Further attention on expansion and differentiation of these cells may facilitate β-cell replacement therapy for diabetes.

我们进一步研究了导管细胞向β细胞分化的机制。尽管Pdx-1主要局限于成年胰腺中的β细胞以调节几种β细胞特异性基因，但在人类肥胖和啮齿动物再生模式中已经报道了导管中增加的Pdx-1蛋白水平。Pdx-1蛋白水平增加的这种一致性意味着胰腺的再生模式重现了胚胎发育，并且新生有助于胰岛质量增加。为了检验我们的假设，即导管中的Pdx-1表达可能是导管细胞分化为β细胞的关键因素，我们通过将CAII-Cre小鼠与Pdx-1flE 2/flE 2小鼠杂交来产生导管特异性Pdx-1敲除小鼠，其中导管中的Pdx-1表达在出生前后被敲除。导管中Pdx-1的失活导致正常生长的β细胞减少，这引起高血糖症和葡萄糖耐量。此外，在再生研究中，在成体中很少看到新的β细胞形成。因此，导管中Pdx-1的活化是分化所需的，并且这些分化的β细胞有助于新生期的β细胞密集生长和成人的损伤。我们的研究为胰管来源的β细胞的代偿功能提供了明确的证据，这些发现将鼓励进一步探索胰管细胞作为胰岛再生的来源。进一步关注这些细胞的扩增和分化可能有助于糖尿病的β细胞替代疗法。