Glucagon Like Peptide-1-Directed Human Embryonic Stem Cells Differentiation Into Insulin-Producing Cells Via Hedgehog, cAMP, and PI3K Pathways
Glucagon Like Peptide-1-Directed Human Embryonic Stem Cells Differentiation Into Insulin-Producing Cells Via Hedgehog, cAMP, and PI3K Pathways
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DOI：
10.1097/mpa.0b013e3181bc30dd
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发表时间：
2010-04-01
期刊：
影响因子：
2.9
通讯作者：
Go, Vay Liang W.
中科院分区：
文献类型：
--
作者：
Hui, Hongxiang;Tang, Yongming G.;Go, Vay Liang W.
目的：胰高血糖素样肽-1（glucagonlike peptide-1，GLP-1）可诱导灵长类胚胎干细胞（embryonic stem cell，ES）分化为胰岛素分泌细胞，这一点已被多个研究小组报道，并被我们的观察所证实。方法：为了进一步阐明这一分化过程的细节和参与这一分化的信号通路，我们用GLP-1诱导人ES细胞HUES 1分化为胰岛素分泌细胞。干细胞标志物（人端粒酶逆转录酶和八聚体-4）表达下调的时间依赖性模式，以及多种A细胞特异性蛋白（胰岛素、葡萄糖激酶、葡萄糖转运蛋白2型和胰岛十二指肠同源框1）和刺猬信号分子（印度刺猬、音刺猬和刺猬受体，补丁）的出现已被确定。与刺猬信号抑制剂cytopamine的共处理能够阻断这种分化，提供了证据表明刺猬信号通路参与GLP-1诱导的分化。我们还观察到在GLP-1诱导的ES细胞分化中激活蛋白1、血清反应元件-1、DNA结合转录因子和cAMP反应元件的转录物增加。其特异性抑制剂的抑制作用表明，环磷酸腺苷和磷脂酰肌醇-3-激酶途径，但不是丝裂原活化蛋白激酶途径，所需的诱导分化的ES cells.Conclusions：这些数据支持GLP-1指导人ES细胞分化为胰岛素产生细胞通过刺猬，环磷酸腺苷，磷脂酰肌醇-3-激酶途径。
Objectives: That glucagonlike peptide-1 (GLP-1) induces differentiation of primate embryonic stem (ES) cells into insulin-producing cells has been reported by several groups and also confirmed with our observations.Methods: To further elucidate the process in detail and the signaling pathways involved in this differentiation, we induced human ES cells HUES1 differentiated into insulin secretion cells by GLP-1 treatment.Results: A time-dependent pattern of down expression of the stem cell markers (human telomerase reverse transcriptase and octamer-4), and the appearance of multiple A-cell-specific proteins (insulin, glucokinase, glucose transporter, type 2, and islet duodenal homeobox 1) and hedgehog signal molecules (Indian hedgehog, sonic hedgehog, and hedgehog receptor, patched) have been identified. Cotreatment with hedgehog signal inhibitor cytopamine was able to block this differentiation, providing evidence of the involvement of the hedgehog signaling pathway in GLP-1-induced differentiation. We also observed increased transcripts of the transcription factors of activator protein 1, serum response element-1, DNA-binding transcription factors, and cAMP response element in GLP-1-induced ES cell differentiation. Inhibition profile by its specific inhibitors indicated that the cyclic adenosine monophosphate and phosphatidylinositol-3-kinase pathways, but not the mitogen-activated protein kinase pathway, were required for the induced differentiation of ES cells.Conclusions: These data support that GLP-1 directs human ES cell differentiation into insulin-producing cells via hedgehog, cyclic adenosine monophosphate, and phosphatidylinositol-3-kinase pathways.