系统性识别人诱导多能干细胞生成的障碍。
Systematic identification of barriers to human iPSC generation.
机构信息
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Ob/Gyn and Pathology, Center for Reproductive Sciences, and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
出版信息
Cell. 2014 Jul 17;158(2):449-461. doi: 10.1016/j.cell.2014.05.040.
Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) holds enormous promise for regenerative medicine. To elucidate endogenous barriers limiting this process, we systematically dissected human cellular reprogramming by combining a genome-wide RNAi screen, innovative computational methods, extensive single-hit validation, and mechanistic investigation of relevant pathways and networks. We identify reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion. Specific a disintegrin and metalloproteinase (ADAM) proteins inhibit reprogramming, and the disintegrin domain of ADAM29 is necessary and sufficient for this function. Clathrin-mediated endocytosis can be targeted with small molecules and opposes reprogramming by positively regulating TGF-β signaling. Genetic interaction studies of endocytosis or ubiquitination reveal that barrier pathways can act in linear, parallel, or feedforward loop architectures to antagonize reprogramming. These results provide a global view of barriers to human cellular reprogramming.
体细胞重编程为诱导多能干细胞（iPSCs）在再生医学中具有巨大的应用前景。为了阐明限制这一过程的内源性障碍，我们通过结合全基因组 RNAi 筛选、创新的计算方法、广泛的单一命中验证以及相关途径和网络的机制研究，系统地剖析了人类细胞重编程。我们确定了重编程障碍，包括涉及转录、染色质调节、泛素化、去磷酸化、囊泡运输和细胞黏附的基因。特定的去整合素和金属蛋白酶（ADAM）蛋白抑制重编程，并且 ADAM29 的去整合素结构域对于该功能是必需和充分的。网格蛋白介导的内吞作用可以用小分子靶向，并且通过正向调节 TGF-β 信号来对抗重编程。内吞作用或泛素化的遗传相互作用研究表明，障碍途径可以以线性、平行或前馈环结构起作用，以拮抗重编程。这些结果提供了人类细胞重编程障碍的全局视图。
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