Small molecule AT7867 proliferates PDX1-expressing pancreatic progenitor cells derived from human pluripotent stem cells
Small molecule AT7867 proliferates PDX1-expressing pancreatic progenitor cells derived from human pluripotent stem cells
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DOI：
10.1016/j.scr.2017.08.010
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发表时间：
2017-10-01
影响因子：
1.2
通讯作者：
Osafune, Kenji
中科院分区：
文献类型：
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作者：
Kimura, Azuma;Toyoda, Taro;Osafune, Kenji
虽然胰岛移植在1型糖尿病（T1D）患者中实现了胰岛素非依赖性，但其广泛应用受到供体组织稀缺的限制。胰腺祖细胞（PPC）在发育过程中产生胰腺中的所有细胞类型。已显示源自人多能干细胞的PPC在体外和体内均分化成功能性β细胞，并且至少在小鼠中逆转高血糖症。因此，PPC具有作为细胞治疗的替代细胞来源的巨大潜力，并且鉴定促进PPC增殖的化合物可以在临床环境中提供稳定和大规模的胰腺细胞制备系统。在这里，我们开发并进行了基于细胞的筛选，以鉴定诱导hiPSC衍生的PDX1表达PPC增殖的小分子。筛选鉴定出AT7867，其通过维持高Ki 67（+）细胞比率，在6天内促进PPC增殖约5倍。AT7867诱导的增殖不会导致DNA损伤，如pHH2AX染色所示，并且在PPC中特异性观察到，但在其他细胞类型中未观察到。利用小分子进行PPC增殖的既定平台可能有助于使用再生医学方法开发T1D的细胞疗法。(C)2017作者由Elsevier B.V.出版。这是一篇开放获取的文章，在CC BY许可证下
While pancreatic islet transplantation achieves insulin independence in type 1 diabetes (T1D) patients, its widespread application is limited by donor tissue scarcity. Pancreatic progenitor cells (PPCs) give rise to all cell types in the pancreas during development. PPCs derived from human pluripotent stem cells have been shown to differentiate into functional beta cells both in vitro and in vivo, and to reverse hyperglycemia, at least in mice. Therefore, PPCs have great potential to serve as an alternative cell source for cell therapy, and the identification of compounds that facilitate PPC proliferation could provide stable and large-scale pancreatic cell preparation systems in clinical settings. Here, we developed and performed cell-based screens to identify small molecules that induce the proliferation of hiPSC-derived PDX1-expressing PPCs. The screening identified AT7867, which promoted PPC proliferation approximately five-fold within six days through the maintenance of a high Ki67(+) cell ratio. The induced proliferation by AT7867 does not result in DNA damage, as revealed by pHH2AX staining, and is observed specifically in PPCs but not other cell types. The established platform utilizing small molecules for PPC proliferation may contribute to the development of cell therapy for T1D using a regenerative medicine approach. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license