Ying Qi Long, Nichols Jennifer, Chambers Ian, Smith Austin
Institute for Stem Cell Research, University of Edinburgh, King's Buildings, West Mains Road, EH9 3JQ, Edinburgh, Scotland.
Cell. 2003 Oct 31;115(3):281-92. doi: 10.1016/s0092-8674(03)00847-x.
The cytokine leukemia inhibitory factor (LIF) drives self-renewal of mouse embryonic stem (ES) cells by activating the transcription factor STAT3. In serum-free cultures, however, LIF is insufficient to block neural differentiation and maintain pluripotency. Here, we report that bone morphogenetic proteins (BMPs) act in combination with LIF to sustain self-renewal and preserve multilineage differentiation, chimera colonization, and germline transmission properties. ES cells can be propagated from single cells and derived de novo without serum or feeders using LIF plus BMP. The critical contribution of BMP is to induce expression of Id genes via the Smad pathway. Forced expression of Id liberates ES cells from BMP or serum dependence and allows self-renewal in LIF alone. Upon LIF withdrawal, Id-expressing ES cells differentiate but do not give rise to neural lineages. We conclude that blockade of lineage-specific transcription factors by Id proteins enables the self-renewal response to LIF/STAT3.
细胞因子白血病抑制因子（LIF）通过激活转录因子STAT3来驱动小鼠胚胎干细胞（ES细胞）的自我更新。然而，在无血清培养中，LIF不足以阻止神经分化并维持多能性。在此，我们报告骨形态发生蛋白（BMP）与LIF共同作用以维持自我更新，并保留多谱系分化、嵌合体定植及种系传递特性。使用LIF加BMP，ES细胞可从单细胞进行传代培养，且无需血清或饲养层细胞即可从头衍生。BMP的关键作用是通过Smad途径诱导Id基因的表达。Id的强制表达使ES细胞摆脱对BMP或血清的依赖，并允许仅在LIF中实现自我更新。在撤除LIF后，表达Id的ES细胞会分化，但不会产生神经谱系。我们得出结论，Id蛋白对谱系特异性转录因子的阻断使得细胞能够对LIF/STAT3产生自我更新反应。
