BMP4 regulates pancreatic progenitor cell expansion through Id2
BMP4 regulates pancreatic progenitor cell expansion through Id2
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DOI：
10.1074/jbc.m600526200
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发表时间：
2006-05-12
影响因子：
4.8
通讯作者：
Sarvetnick, N
中科院分区：
文献类型：
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作者：
Hua, H;Zhang, YQ;Sarvetnick, N
DNA结合抑制剂（Id）蛋白结合并抑制碱性螺旋-环-螺旋（bHLH）转录因子的功能，包括那些调节胰腺发育的转录因子。此外，骨形态发生蛋白（BMPs）调节Ids的表达。我们假设BMP4和Id蛋白在上皮祖细胞的扩增和分化中发挥作用。我们证实BMP4诱导Id2的表达，并伴随AR42J胰腺上皮细胞的扩增。此外，在小鼠胰岛再生模型中，中和BMP4显著降低了导管上皮细胞的扩增。BMP4刺激促进Id2与bHLH转录因子NeuroD结合，这是胰岛细胞分化所必需的。因此，我们的研究结果表明，BMP4刺激阻断了内分泌祖细胞的分化，反而促进了它们的扩张，从而揭示了一种新的信号传导模式，解释了胰管上皮祖细胞的扩张和分化之间的平衡。了解bmp和Id的功能机制阐明了胰腺胚胎发生的关键步骤，这是体外扩增胰腺祖细胞的重要知识。
Inhibitor of DNA binding (Id) proteins bind to and inhibit the function of basic helix-loop-helix (bHLH) transcription factors including those that regulate pancreatic development. Moreover, bone morphogenetic proteins (BMPs) regulate the expression of Ids. We hypothesized that BMP4 and Id proteins play a role in the expansion and differentiation of epithelial progenitor cells. We demonstrate that BMP4 induces the expression of Id2 along with the expansion of AR42J pancreatic epithelial cells. Furthermore, neutralization of BMP4 significantly reduced duct epithelial cell expansion in a mouse model of islet regeneration. BMP4 stimulation promotes Id2 binding to the bHLH transcription factor NeuroD, which is required for the differentiation of pancreatic islet cells. Therefore, our results indicate that BMP4 stimulation blocks the differentiation of endocrine progenitor cells and instead promotes their expansion thereby revealing a novel paradigm of signaling explaining the balance between expansion and differentiation of pancreatic duct epithelial progenitors. Understanding the mechanisms of BMPand Id function elucidates a key step during pancreas embryogenesis, which is important knowledge for expanding pancreatic progenitors in vitro.