STAT5 requires the N-domain to maintain hernatopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output
STAT5 requires the N-domain to maintain hernatopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output
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DOI：
10.1016/j.exphem.2007.08.026
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发表时间：
2007-11-01
影响因子：
2.6
通讯作者：
Bunting, Kevin D.
中科院分区：
文献类型：
--
作者：
Liu, Geqiang;Wang, Zhengqi;Bunting, Kevin D.
客观的。信号转导和转录激活因子 5 (STAT5) 是造血发育的关键调节因子，其激活受损与造血和免疫细胞缺陷相关。然而，大部分信息是从基因敲除小鼠中获悉的，这些小鼠仍然保留表达 STAT5 蛋白的潜力，这些蛋白由于替代的内部翻译起始密码子而被 N 末端截短。这些研究的目标是使用基于移植的测定法来分析造血干细胞（HSC 和整个淋巴骨髓发育过程中）STAT5 Delta N 活性的程度。方法。我们直接比较了来自具有表达 STAT5ab Delta N 潜力的小鼠 (STAT5ab(Delta N/Delta N)) 的 E14.5 胎儿肝细胞与完全缺乏 STAT5a 和 STAT5b (STAT5ab (null/null)) 的小鼠。我们还利用了逆转录病毒STAT5ab 无效/无效胎儿肝脏 HSC 的互补，以增强缺乏前 136 个氨基酸的全长 STAT5a 或 STAT5a (STAT5a Delta N)。结果我们报告，STAT5 是 HSC、淋巴细胞和红细胞发育所必需的。我们证明，STAT5ab 无效/无效 HSC 中 STAT5a 的恢复表达提供了强大的选择性优势，可纠正 T 淋巴细胞和 B 淋巴细胞和红细胞。有趣的是，Gr-1(+) 血细胞与 B 淋巴细胞呈负相关，并且两者均通过 STAT5a 表达正常化。相反，STAT5a Delta N 的转导仅提供部分 B 淋巴细胞的发育。结论这些研究明确了 STAT5 在造血过程中维持正常淋巴与骨髓平衡的作用，并强调了此处描述的逆转录病毒互补平台的主要作用。细分对造血至关重要的 N 结构域区域的研究 (C) 2007 ISEH - 血液学和干细胞协会出版。
Objective. Signal transducer and activator of transcription 5 (STAT5) is a critical regulator of hematopoietic development and its impaired activation is associated with hematopoietic and immune cell defects. However, much of this information has been learned from knockout mice that still retain the potential for expression of STAT5 proteins that are N-terminally truncated due to alternative internal translation initiation codons. The goal of these studies was to use transplantation-based assays to analyze the degree of STAT5 Delta N activity in hematopoietic stem cells (HSC and throughout lymphomyeloid development.Methods. We have directly compared E14.5 fetal liver cells from mice with potential to express STAT5ab Delta N (STAT5ab(Delta N/Delta N)) with mice completely lacking STAT5a and STAT5b (STAT5ab (null/null)). We have also utilized retroviral complementation of STAT5ab null/null fetal liver HSC to enforce expression of full-length STAT5a or STAT5a lacking the first 136 amino acids (STAT5a Delta N).Results. We report that STAT5 is required for HSC, lymphocyte, and erythrocyte development. We demonstrate that restored expression of STAT5a in STAT5ab null/null HSC provides a strong selective advantage, correcting T- and B-lymphocyte and erythrocyte development. Interestingly, Gr-l(+) blood cells were inversely correlated with B lymphocytes and both were normalized by STAT5a expression. In contrast, transduction of STAT5a Delta N only provided partial B-lymphocyte development.Conclusions. These studies define the role of STAT5 in maintaining normal lymphoid vs myeloid balance during hematopoiesis and highlight a major role for the N-domain in HSC function. The platform of retroviral complementation described here will be particularly useful for future studies to subdefine the N-domain regions that are critical for hematopoiesis. (C) 2007 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.