The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization
The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization
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DOI：
10.1182/blood-2010-08-300236
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发表时间：
2011-05-26
期刊：
影响因子：
20.3
通讯作者：
Haigh, Jody J.
中科院分区：
文献类型：
--
作者：
Goossens, Steven;Janzen, Viktor;Haigh, Jody J.
Zeb 2（Sip 1/Zfhx 1b）是锌指E-box结合（ZEB）转录抑制因子家族的成员，以前被证明在胚胎发生和肿瘤进展期间调节上皮向间充质转化（EMT）过程。我们在HSC和造血祖细胞（HPC）中发现了高Zeb 2 mRNA表达水平，并使用Tie 2-Cre和Vav-iCre重组小鼠系通过条件性缺失方法检查了Zeb 2在造血中的功能。详细的细胞分析表明，Zeb 2在胚胎的性腺-中肾区的造血簇和HSC形成中是必需的，但对于正常的HSC/HPC分化是必需的。此外，Zeb 2缺陷的HSC/HPC不能适当地定殖胎肝和/或骨髓，并且显示与增加的β 1整合素和Cxcr 4表达相关的增强的粘附特性。此外，Zeb 2的缺失导致胚胎（Tie 2-Cre）和围产期（Vav-icre）的致命性，由于严重的头部老化和血管生成素-1水平降低，随后，不适当的周细胞覆盖的头部脉管系统。这些结果揭示了Zeb 2在胚胎造血中的重要作用，并提示Zeb 2在成人造血相关病理中的作用。（血。2011; 117（21）：5620-5630）
Zeb2 (Sip1/Zfhx1b) is a member of the zinc-finger E-box-binding (ZEB) family of transcriptional repressors previously demonstrated to regulate epithelial-to-mesenchymal transition (EMT) processes during embryogenesis and tumor progression. We found high Zeb2 mRNA expression levels in HSCs and hematopoietic progenitor cells (HPCs), and examined Zeb2 function in hematopoiesis through a conditional deletion approach using the Tie2-Cre and Vav-iCre recombination mouse lines. Detailed cellular analysis demonstrated that Zeb2 is dispensable for hematopoietic cluster and HSC formation in the aorta-gonadomesonephros region of the embryo, but is essential for normal HSC/HPC differentiation. In addition, Zeb2-deficient HSCs/HPCs fail to properly colonize the fetal liver and/or bone marrow and show enhanced adhesive properties associated with increased beta 1 integrin and Cxcr4 expression. Moreover, deletion of Zeb2 resulted in embryonic (Tie2-Cre) and perinatal (Vav-icre) lethality due to severe cephalic hemorrhaging and decreased levels of angiopoietin-1 and, subsequently, improper pericyte coverage of the cephalic vasculature. These results reveal essential roles for Zeb2 in embryonic hematopoiesis and are suggestive of a role for Zeb2 in hematopoietic-related pathologies in the adult. (Blood. 2011; 117(21): 5620-5630)