Enhanced hematopoietic differentiation of embryonic stem cells conditionally expressing Stat5
Enhanced hematopoietic differentiation of embryonic stem cells conditionally expressing Stat5
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DOI：
10.1073/pnas.1734140100
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发表时间：
2003-09-30
影响因子：
11.1
通讯作者：
Daley, GQ
中科院分区：
文献类型：
--
作者：
Kyba, M;Perlingeiro, RCR;Daley, GQ
信号转导子Stat5在造血分化和造血干细胞功能调节中起关键作用。为了评估Stat5信号传导在最早期造血祖细胞中的作用，我们已经产生了一种胚胎干细胞系，其中Stat5信号传导可以用多西环素诱导。在造血谱系的起源点（从胚状体分化的第4天至第6天）处的异位Stat5活化显著增强具有集落形成潜力的造血祖细胞的数量。它这样做没有显着改变造血细胞的总数或凋亡，这表明细胞内在的影响Stat5的发展潜力或克隆形成的这个群体。从第6天胚状体开始，在Stat5信号传导的影响下，半贴壁细胞群体可以在0P9基质细胞上扩增，所述0P9基质细胞由原始造血母细胞组成，具有正在进行的主要是髓样分化。当这些细胞被注射到致死性照射的小鼠，他们植入短暂的强力霉素依赖性的方式。这些结果表明，造血承诺的胚胎干细胞可以增强Stat5介导的信号，并突出了工程组织特异性分化的干细胞的操纵信号通路的各个组件的效用。
The signal transducer Stat5 plays a key role in the regulation of hematopoietic differentiation and hematopoietic stem cell function. To evaluate the effects of Stat5 signaling in the earliest hematopoietic progenitors, we have generated an embryonic stem cell line in which Stat5 signaling can be induced with doxycycline. Ectopic Stat5 activation at the point of origin of the hematopoietic lineage (from day 4 to day 6 of embryoid body differentiation) significantly enhances the number of hematopoietic progenitors with colony-forming potential. It does so without significantly altering total numbers or apoptosis of hematopoietic cells, suggesting a cell-intrinsic effect of Stat5 on either the developmental potential or clonogenicity of this population. From day-6 embryoid bodies, under the influence of Stat5 signaling, a population of semiadherent cells can be expanded on OP9 stromal cells that is comprised of primitive hematopoietic blast cells with ongoing, mainly myeloid, differentiation. When these cells are injected into lethally irradiated mice, they engraft transiently in a doxycycline-dependent manner. These results demonstrate that the hematopoietic commitment of embryonic stem cells may be augmented by a Stat5-mediated signal, and highlight the utility of manipulating individual components of signaling pathways for engineering tissue-specific differentiation of stem cells.