Glucagon-like peptide-1 differentiation of primate embryonic stem cells into insulin-producing cells
Glucagon-like peptide-1 differentiation of primate embryonic stem cells into insulin-producing cells
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DOI：
10.1089/ten.2006.12.2105
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发表时间：
2006-08-01
影响因子：
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通讯作者：
Sasaki, Katsunori
中科院分区：
文献类型：
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作者：
Yue, Fengming;Cui, Li;Sasaki, Katsunori
本研究旨在探讨胰升糖素样肽-1(GLP-1)是否能促进巢蛋白筛选的胚胎干细胞分化为胰岛素分泌细胞。我们的实验策略始于从类胚体中生产高度丰富的巢蛋白阳性细胞群。加入GLP-1后，这些细胞分化为胰岛素分泌细胞。诱导培养形成胰岛样细胞团。这些巢蛋白阳性的细胞来源的ICCs表达许多β细胞系基因，包括胰岛素、GLUT-2、胰腺十二指肠同源盒-1蛋白(PDX-1)、胰岛淀粉样多肽(IAPP)、神经原蛋白3(NGN3)以及α、γ和三角洲细胞基因标记。ICCs细胞胰岛素蛋白表达增加，胰岛素释放呈葡萄糖依赖性，胰岛素与C肽共表达。巢蛋白/胰岛素和巢蛋白/PDX-1共同表达是ICCs的特征。GLP-1组大鼠胰腺相关基因和蛋白表达水平及胰岛素分泌水平均高于正常对照组。GLP-1已被证明参与刺激转录因子PDX-1下游的信号通路，通过增加其蛋白质和信使RNA水平。在体内，ICCs显示了逆转糖尿病严重联合免疫缺陷(SCID)小鼠高血糖的能力。我们得出结论：GLP-1通过上调PDX-1的表达，诱导巢蛋白阳性的前体胚胎干细胞分化为胰岛素分泌细胞。这种方法可能会在糖尿病的干细胞治疗中有未来的应用。
The present study was performed to determine whether glucagon-like peptide-1 (GLP-1) stimulates differentiation of nestin-selected embryonic stem cells into insulin-producing cells. Our experimental strategy began with the production of a highly enriched population of nestin-positive cells from embryoid bodies. These cells differentiated into insulin-producing cells after addition of GLP-1. Islet-like cell clusters (ICCs) formed in inducing culture. These nestin-positive cell-derived ICCs expressed numerous beta-cell lineage genes, including insulin; Glut-2; pancreatic duodenal homebox-1 protein (PDX-1); islet amyloid polypeptide (IAPP); neurogenin 3 (ngn3); and alpha, gamma, and delta cell gene markers. Cells of ICCs showed increased insulin protein expression, glucose-dependent insulin release, and coexpression of insulin and C-peptide. In addition, ICCs were characterized by coexpression of nestin/insulin and nestin/PDX-1. The levels of pancreas-related gene and protein expression and insulin secretion in the GLP-1 group were stronger than those in the normal controls. GLP-1 has been shown to be involved in stimulating the signaling pathways downstream of the transcription factor PDX-1, by increasing its protein and messenger RNA levels. In vivo, ICCs displayed the ability to reverse hyperglycemia in diabetic severe combined immunodeficiency (SCID) mice. We concluded that GLP-1 induced differentiation of nestin-positive progenitor embryonic stem cells into insulin-producing cells, which was achieved by upregulation of PDX-1 expression. This method may have future applications in stem cell therapy of diabetes.