Bone Heather K, Damiano Teresa, Bartlett Stephen, Perry Alexis, Letchford Julie, Ripoll Yolanda Sanchez, Nelson Adam S, Welham Melanie J
Department of Pharmacy and Pharmacology, Centre for Regenerative Medicine, University of Bath, Bath, UK.
Chem Biol. 2009 Jan 30;16(1):15-27. doi: 10.1016/j.chembiol.2008.11.003.
The ability to propagate embryonic stem cells (ESCs) while maintaining their pluripotency is critical if their potential use in regenerative medicine is to be realized. The mechanisms controlling ESC self-renewal are under intense investigation, and glycogen synthase kinase 3 (GSK-3) has been implicated in regulating both self-renewal and differentiation. To clarify its role in ESCs we have used chemical genetics. We synthesized a series of bisindolylmaleimides, a subset of which inhibit GSK-3 in murine ESCs and robustly enhance self-renewal in the presence of leukemia inhibitory factor (LIF) and serum, but not in the absence of LIF. Importantly, these molecules appear selective for GSK-3 and do not perturb other signaling pathways regulating self-renewal. Our study clarifies the functional importance of GSK-3 in regulation of ESC self-renewal and provides tools for investigating its role further.
如果要实现胚胎干细胞（ESC）在再生医学中的潜在应用，那么在维持其多能性的同时进行增殖的能力至关重要。目前正在深入研究控制ESC自我更新的机制，糖原合酶激酶3（GSK-3）已被认为参与调节自我更新和分化。为了阐明其在ESC中的作用，我们采用了化学遗传学方法。我们合成了一系列双吲哚马来酰胺，其中一部分能够抑制小鼠ESC中的GSK-3，并在白血病抑制因子（LIF）和血清存在的情况下显著增强自我更新能力，但在没有LIF的情况下则不然。重要的是，这些分子似乎对GSK-3具有选择性，不会干扰调节自我更新的其他信号通路。我们的研究阐明了GSK-3在调节ESC自我更新中的功能重要性，并为进一步研究其作用提供了工具。
