Kristensen David Møbjerg, Kalisz Mark, Nielsen Jens Høiriis
Department of Medical Biochemistry and Genetics, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
APMIS. 2005 Nov-Dec;113(11-12):756-72. doi: 10.1111/j.1600-0463.2005.apm_391.x.
Cytokines play a central role in maintaining self-renewal in mouse embryonic stem (ES) cells through a member of the interleukin-6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK-STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric complex with LIF and the class I cytokine receptor LIF receptor beta. STAT3 has been shown to play a crucial role in self-renewal in mouse ES cells probably by induction of c-myc expression. Thus, ablation of STAT3 activation leads to differentiation. However, important connections between STAT3 and other signalling pathways have been documented. In addition, gp130 activation leads to both PI3K and Src activation. The canonical Wnt pathway is sufficient to maintain self-renewal of both human ES cells and mouse ES cells. It seems quite possible that the main pathway maintaining self-renewal in ES cells is the Wnt pathway, while the LIF-JAK-STAT3 pathway is present in mouse cells as an adaptation for sustaining self-renewal during embryonic diapause, a condition of delayed implantation in mammals. In keeping with this scenario, the Wnt pathway has been shown to elevate the level of c-myc. Thus, the two pathways seem to converge on c-myc as a common target to promote self-renewal. Whereas LIF does not seem to stimulate self-renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem cell-specific factors.
细胞因子在通过白细胞介素-6型细胞因子家族的一个成员——白血病抑制因子（LIF）维持小鼠胚胎干细胞（ES细胞）的自我更新中发挥核心作用。LIF通过I类细胞因子受体gp130激活JAK-STAT3信号通路，gp130与LIF和I类细胞因子受体LIF受体β形成三聚体复合物。STAT3已被证明可能通过诱导c-myc表达在小鼠ES细胞的自我更新中起关键作用。因此，STAT3激活的缺失会导致细胞分化。然而，STAT3与其他信号通路之间的重要联系已有文献记载。此外，gp130激活会导致PI3K和Src激活。经典的Wnt信号通路足以维持人类ES细胞和小鼠ES细胞的自我更新。似乎很有可能维持ES细胞自我更新的主要信号通路是Wnt信号通路，而LIF-JAK-STAT3信号通路在小鼠细胞中存在是为了适应胚胎滞育期间维持自我更新，胚胎滞育是哺乳动物中一种延迟着床的状态。与此情况相符的是，Wnt信号通路已被证明能提高c-myc的水平。因此，这两条信号通路似乎都以c-myc为共同靶点来促进自我更新。虽然LIF似乎不会刺激人类胚胎干细胞的自我更新，但不能排除其他细胞因子也参与其中。越来越多的细胞因子和受体通过JAK、STAT和SOCS进行信号传导，其多效性作用在干细胞中表现出相当大的冗余性（功能重叠）、补偿性和可塑性，这与干细胞受信号事件强度和持续时间的定量变化所调控的观点一致，这些信号事件在其他细胞类型中也存在，而非由性质不同的干细胞特异性因子所调控。
