A small molecule that directs differentiation of human ESCs into the pancreatic lineage
A small molecule that directs differentiation of human ESCs into the pancreatic lineage
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DOI：
10.1038/nchembio.154
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发表时间：
2009-04-01
影响因子：
14.8
通讯作者：
Melton, Douglas
中科院分区：
文献类型：
--
作者：
Chen, Shuibing;Borowiak, Malgorzata;Melton, Douglas
从胚胎干细胞（ESCs）逐步分化为功能性的胰岛素分泌β细胞将确定β细胞发育的关键步骤，并且可能对糖尿病患者的移植治疗有用。这一过程中的一个关键步骤是产生胰腺祖细胞——表达Pdx1并能产生胰腺所有细胞类型的细胞。高通量化学筛选确定了一种小分子（-）-吲哚并咔唑-V，它能诱导大量表达Pdx1的细胞从人胚胎干细胞分化出来。表达Pdx1的细胞表达其他胰腺标志物，并在体外和体内参与内分泌、外分泌和导管细胞的形成。进一步的分析表明，（-）-吲哚并咔唑-V在胰腺发育的一个特定阶段起作用，从定型内胚层诱导产生胰腺祖细胞。这项研究描述了一个用于研究人胚胎干细胞分化的化学筛选平台，并展示了一种细胞群体的产生，这是制造β细胞道路上的一个关键里程碑。
Stepwise differentiation from embryonic stem cells (ESCs) to functional insulin-secreting beta cells will identify key steps in beta-cell development and may yet prove useful for transplantation therapy for diabetics. An essential step in this schema is the generation of pancreatic progenitors-cells that express Pdx1 and produce all the cell types of the pancreas. High-content chemical screening identified a small molecule, (-)-indolactam V, that induces differentiation of a substantial number of Pdx1-expressing cells from human ESCs. The Pdx1-expressing cells express other pancreatic markers and contribute to endocrine, exocrine and duct cells, in vitro and in vivo. Further analyses showed that (-)-indolactam V works specifically at one stage of pancreatic development, inducing pancreatic progenitors from definitive endoderm. This study describes a chemical screening platform to investigate human ESC differentiation and demonstrates the generation of a cell population that is a key milepost on the path to making beta cells.