Induced Pluripotent Stem Cells Reprogrammed with Three Inhibitors Show Accelerated Differentiation Potentials with High Levels of 2-Cell Stage Marker Expression
Induced Pluripotent Stem Cells Reprogrammed with Three Inhibitors Show Accelerated Differentiation Potentials with High Levels of 2-Cell Stage Marker Expression
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DOI：
10.1016/j.stemcr.2018.12.018
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发表时间：
2019-01
影响因子：
5.9
通讯作者：
Koji Nishihara;Takahiro Shiga;Eri Nakamura;Tomohiko Akiyama;Takashi Sasaki;Sadafumi Suzuki;M. Ko;N. Tada;H. Okano;W. Akamatsu
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文献类型：
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作者：
Koji Nishihara;Takahiro Shiga;Eri Nakamura;Tomohiko Akiyama;Takashi Sasaki;Sadafumi Suzuki;M. Ko;N. Tada;H. Okano;W. Akamatsu
虽然多能干细胞可以产生各种类型的分化细胞，但目前尚不清楚为什么来自多能干细胞的谱系承诺干细胞/祖细胞被减速，以及为什么胚胎干细胞(ESC)/诱导多能干细胞（iPSC）来源的细胞与来自胚胎/成体组织的体内同类细胞相比，它们的分化抗性倾向占主导地位。在这项研究中，我们证明了使用成纤维细胞生长因子4-丝裂原激活的蛋白激酶级联的三种化学抑制剂和GSK3β (3i)进行重编程和维持的iPSCs可以比不使用3i化学物质进行重编程的iPSCs更有效地分化为所有三种胚层，即使它们在重编程后使用3i化学物质维持。虽然用3i重编程的iPSCs增加了zscan4阳性细胞的数量，但在没有3i重编程的iPSCs中，zscan4阳性细胞没有加速分化能力。这些观察结果表明，在重编程期间暴露3i决定了iPSCs的加速分化/成熟潜力，并稳定地维持在不同的状态。
Although pluripotent stem cells can generate various types of differentiated cells, it is unclear why lineage-committed stem/progenitor cells derived from pluripotent stem cells are decelerated and why the differentiation-resistant propensity of embryonic stem cell (ESC)/induced pluripotent stem cell (iPSC)-derived cells is predominant compared with thein vivoequivalents derived from embryonic/adult tissues. In this study, we demonstrated that iPSCs reprogrammed and maintained with three chemical inhibitors of the fibroblast growth factor 4-mitogen-activated protein kinase cascade and GSK3β (3i) could be differentiated into all three germ layers more efficiently than the iPSCs reprogrammed without the 3i chemicals, even though they were maintained with 3i chemicals once they were reprogrammed. Although the iPSCs reprogrammed with 3i had increased numbers of Zscan4-positive cells, the Zscan4-positive cells among iPSCs that were reprogrammed without 3i did not have an accelerated differentiation ability. These observations suggest that 3i exposure during the reprogramming period determines the accelerated differentiation/maturation potentials of iPSCs that are stably maintained at the distinct state.