Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells
Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells
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DOI：
10.1016/j.scr.2011.10.002
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发表时间：
2012-03-01
影响因子：
1.2
通讯作者：
Hosoya, Masaki
中科院分区：
文献类型：
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作者：
Kunisada, Yuya;Tsubooka-Yamazoe, Noriko;Hosoya, Masaki
人类诱导多能干细胞（hiPS）在药物发现和细胞治疗方面具有潜在的用途，包括产生用于糖尿病研究和治疗的胰腺β细胞。在这项研究中，我们开发了一个简单的协议，从hiPS细胞产生胰岛素产生细胞。用激活素A和GSK 3 β抑制剂处理增强了有效的内胚层分化，然后用视黄酸、骨形态发生蛋白抑制剂和转化生长因子β（TGF-β）抑制剂联合处理诱导了来自定形内胚层的胰腺祖细胞的有效分化。胰腺祖细胞标志物PDX 1和NGN 3的表达在该步骤显著增加，并且大多数细胞对抗PDX 1抗体呈阳性。此外，发现包括毛喉素、地塞米松和TGF-β抑制剂在内的几种化合物可诱导胰腺祖细胞分化为胰岛素产生细胞。通过与这些化合物的联合治疗，超过10%的细胞变得胰岛素阳性。分化的细胞分泌人c肽响应于各种胰岛素促分泌素。此外，我们检查的所有五种hiPS细胞系都显示出利用该方案有效分化为胰岛素产生细胞。(C)2011 Elsevier B. V.保留所有权利。
Human induced pluripotent stem (hiPS) cells have potential uses for drug discovery and cell therapy, including generation of pancreatic beta-cells for diabetes research and treatment. In this study, we developed a simple protocol for generating insulin-producing cells from hiPS cells. Treatment with activin A and a GSK3 beta inhibitor enhanced efficient endodermal differentiation, and then combined treatment with retinoic acid, a bone morphogenic protein inhibitor, and a transforming growth factor-beta (TGF-beta) inhibitor induced efficient differentiation of pancreatic progenitor cells from definitive endoderm. Expression of the pancreatic progenitor markers PDX1 and NGN3 was significantly increased at this step and most cells were positive for anti-PDX1 antibody. Moreover, several compounds, including forskolin, dexamethasone, and a TGF-beta inhibitor, were found to induce the differentiation of insulin-producing cells from pancreatic progenitor cells. By combined treatment with these compounds, more than 10% of the cells became insulin positive. The differentiated cells secreted human c-peptide in response to various insulin secretagogues. In addition, all five hiPS cell lines that we examined showed efficient differentiation into insulin-producing cells with this protocol. (C) 2011 Elsevier B.V. All rights reserved.