Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Oct4 and Klf4 with Small-Molecule Compounds
Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Oct4 and Klf4 with Small-Molecule Compounds
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DOI：
10.1016/j.stem.2008.10.004
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发表时间：
2008-11-06
期刊：
影响因子：
23.9
通讯作者：
Ding, Sheng
中科院分区：
文献类型：
--
作者：
Shi, Yan;Desponts, Caroline;Ding, Sheng
体细胞可通过四种转录因子（Oct4/Sox2/Klf4/c - Myc或Oct4/Sox2/Nanog/LIN28）的组合诱导为多能干细胞（iPSCs）。这为获取用于各种治疗和研究应用的患者特异性细胞提供了一个可行的平台。然而，由于效率和病毒基因组整合相关的缺陷，这种方法要在治疗上具有相关性还存在一些问题。最近有研究表明，用Oct4/Klf4转导的神经祖细胞（NPCs）可被重编程为iPSCs。然而，NPCs内源性表达Sox2，这可能在没有外源性Sox2的情况下促进重编程。在本研究中，我们发现了一种小分子组合BIX - 01294和BayK8644，它能够使Oct4/Klf4转导的小鼠胚胎成纤维细胞重编程，这些细胞内源性不表达重编程所必需的因子。这项研究表明，通过表型筛选确定的小分子能够弥补关键因子（如Sox2）的病毒转导，并提高重编程效率。
Somatic cells can be induced into pluripotent stem cells (iPSCs) with a combination of four transcription factors, Oct4/Sox2/Klf4/c-Myc or Oct4/Sox2/Nanog/LIN28. This provides an enabling platform to obtain patient-specific cells for various therapeutic and research applications. However, several problems remain for this approach to be therapeutically relevant due to drawbacks associated with efficiency and viral genome integration. Recently, it was shown that neural progenitor cells (NPCs) transduced with 0ct4/Klf4 can be reprogrammed into iPSCs. However, NPCs express Sox2 endogenously, possibly facilitating reprogramming in the absence of exogenous Sox2. In this study, we identified a small-molecule combination, BIX-01294 and BayK8644, that enables reprogramming of Oct4/Klf4-transduced mouse embryonic fibroblasts, which do not endogenously express the factors essential for reprogramming. This study demonstrates that small molecules identified through a phenotypic screen can compensate for viral transduction of critical factors, such as Sox2, and improve reprogramming efficiency.