Maintenance of pluripotency in human embryonic stem cells is STAT3 independent
Maintenance of pluripotency in human embryonic stem cells is STAT3 independent
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DOI：
10.1634/stemcells.22-4-522
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发表时间：
2004-01-01
期刊：
影响因子：
5.2
通讯作者：
Hayek, A
中科院分区：
文献类型：
--
作者：
Humphrey, RK;Beattie, GM;Hayek, A
小鼠胚胎干细胞（mES）中“干性”的保持是通过需要gp 130受体、细胞因子的白介素-6（IL-6）家族和Janus激酶-信号转导和激活剂（JAK/STAT）途径的信号转导途径来维持的。调节人类胚胎干细胞（hFS）“干性”的因子和信号通路仍有待阐明。在这里，我们报告说，STAT 3激活是不足以阻止hES细胞分化时，细胞生长在小鼠饲养细胞或当他们用条件培养基从饲养细胞处理。人ES细胞在细胞因子IL-6家族成员（包括白血病抑制因子（LIF）和IL-6）存在下或在设计细胞因子hyper-IL-6存在下分化，hyper-IL-6是可溶性白细胞介素-6受体（IL-6 R）和IL-6的复合物，具有大大增强的生物活性。人ES细胞表达LIF、IL-6和gp 130受体以及下游信号分子。用gp 130细胞因子刺激人和小鼠ES细胞导致下游ERK 1、ERK 2和Akt激酶以及STAT 3转录因子的强烈磷酸化。在gp 130依赖性信号传导过程中，在hES细胞中观察到多能性标志物Nanog、Oct-4和TRA-1-60的丢失，表明通过该途径的信号传导不足以阻止分化的开始。这些数据强调了鼠细胞与hES细胞需求的根本差异。此外，这些数据表明，在小鼠饲养层细胞的条件培养基中存在一种尚未鉴定的因子，其作用是以STAT 3非依赖性方式维持hES细胞更新。
The preservation of "stemness" in mouse embryonic stem (mES) cells is maintained through a signal transduction pathway that requires the gp130 receptor, the interleukin-6 (IL-6) family of cytokines, and the Janus Kinase-signal transducer and activator (JAK/STAT) pathway. The factors and signaling pathways that regulate "stemness" in human embryonic stem (hFS) cells remain to be elucidated. Here we report that STAT3 activation is not sufficient to block hES cell differentiation when the cells are grown on mouse feeder cells or when they are treated with conditioned media from feeder cells. Human ES cells differentiate in the presence of members of the IL-6 family of cytokines including leukemia inhibitory factor (LIF) and IL-6 or in the presence of the designer cytokine hyper-IL-6, which is a complex of soluble interleukin-6 receptor (IL-6R) and IL-6 with greatly enhanced bioactivity. Human ES cells express LIF, IL-6, and gp130 receptors, as well as the downstream signaling molecules. Stimulation of human and mouse ES cells with gp130 cytokines resulted in a robust phosphorylation of downstream ERK1, ERK2, and Akt kinases, as well as the STAT3 transcription factor. Loss of the pluripotency markers Nanog, Oct-4, and TRA-1-60 was observed in hES cells during gp130-dependent signaling, indicating that signaling through this pathway is insufficient to prevent the onset of differentiation. These data underscore a fundamental difference in requirements of murine versus hES cells. Furthermore, the data demonstrate the existence of an as-yet-unidentified factor in the conditioned media of mouse feeder layer cells that acts to maintain hES cell renewal in a STAT3-independent manner.