长时间的Mek1/2抑制会损害胚胎干细胞的发育潜力
Jiho Choi1,2,3,4, Aaron J Huebner1,2,3,4, Kendell Clement3,4,5
1Massachusetts General Hospital Department of Molecular Biology, Boston, Massachusetts 02114, USA.
Nature
|July 27, 2017
概括
在2i/L介质中长期培养小鼠胚胎干细胞 (ES细胞) 会导致不可逆转的表观遗传变化,损害发育潜力. 用Src抑制代替Mek1/ 2抑制可以保持ES细胞的完整性和功能.
科学领域:
- 干细胞生物学
- 表观遗传学
- 发育生物学
背景情况:
- 用两种小分子抑制剂 (2i) 和白血病抑制因子 (LIF) 培养的原始小鼠胚胎干细胞 (ES细胞) 模仿内部细胞质量 (ICM).
- 在体内ICM的短暂性质引发了关于在体内培养的原始ES细胞的长期稳定性和功能的问题.
研究的目的:
- 研究长期纯粹的ES细胞培养对其表观遗传和基因组稳定性的影响.
- 确定这些变化背后的分子机制,并探索维持ES细胞发展潜力的策略.
主要方法:
- 在不同的条件下长期培养雄性和雌性小鼠ES细胞 (2i/L,血清+LIF).
- 对表观遗传修饰,基因组完整性和发展潜力的分析.
- 涉及抑制特定信号通路的机制研究 (Mek1/2, Src).
主要成果:
- 在男性ES细胞中持续培养2i/ L导致不可逆转的表观遗传和基因组变化,降低了发育潜力.
- 在血清+LIF介质中的雌性ES细胞在2i/L中表现出与雄性ES细胞相似的有害变化.
- 部分通过DNA甲基转移酶的降低调节被确定为这些负面影响的主要驱动因素.
- 将Mek1/ 2抑制剂替换为Src抑制剂可以保持表观遗传和基因组完整性,从而保持发育潜力.
结论:
- 短期的Mek1/ 2抑制可以在ES细胞中建立类似ICM的状态.
- 长时间的Mek1/ 2抑制会导致不可逆转的表观遗传变化,损害ES细胞的发育能力.
- 在长时间培养过程中,Src抑制提供了一个潜在的替代方法来维持ES细胞的多能性和发育潜力.
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