Kaimakis Polynikis, de Pater Emma, Eich Christina, Solaimani Kartalaei Parham, Kauts Mari-Liis, Vink Chris S, van der Linden Reinier, Jaegle Martine, Yokomizo Tomomasa, Meijer Dies, Dzierzak Elaine
Erasmus Medical Center Stem Cell Institute, Departments of Cell Biology and Genetics, and.
Erasmus Medical Center Stem Cell Institute, Departments of Cell Biology and Genetics, and Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands; and.
Blood. 2016 Mar 17;127(11):1426-37. doi: 10.1182/blood-2015-10-673749. Epub 2016 Feb 1.
The Gata2 transcription factor is a pivotal regulator of hematopoietic cell development and maintenance, highlighted by the fact that Gata2 haploinsufficiency has been identified as the cause of some familial cases of acute myelogenous leukemia/myelodysplastic syndrome and in MonoMac syndrome. Genetic deletion in mice has shown that Gata2 is pivotal to the embryonic generation of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). It functions in the embryo during endothelial cell to hematopoietic cell transition to affect hematopoietic cluster, HPC, and HSC formation. Gata2 conditional deletion and overexpression studies show the importance of Gata2 levels in hematopoiesis, during all developmental stages. Although previous studies of cell populations phenotypically enriched in HPCs and HSCs show expression of Gata2, there has been no direct study of Gata2 expressing cells during normal hematopoiesis. In this study, we generate a Gata2Venus reporter mouse model with unperturbed Gata2 expression to examine the hematopoietic function and transcriptome of Gata2 expressing and nonexpressing cells. We show that all the HSCs are Gata2 expressing. However, not all HPCs in the aorta, vitelline and umbilical arteries, and fetal liver require or express Gata2. These Gata2-independent HPCs exhibit a different functional output and genetic program, including Ras and cyclic AMP response element-binding protein pathways and other Gata factors, compared with Gata2-dependent HPCs. Our results, indicating that Gata2 is of major importance in programming toward HSC fate but not in all cells with HPC fate, have implications for current reprogramming strategies.
Gata2转录因子是造血细胞发育和维持的关键调节因子，这一事实突出表现在Gata2单倍体不足已被确定为一些家族性急性髓性白血病/骨髓增生异常综合征病例以及单核巨噬细胞综合征的病因。小鼠基因敲除研究表明，Gata2对造血干细胞（HSC）和造血祖细胞（HPC）的胚胎生成至关重要。它在胚胎期内皮细胞向造血细胞转变过程中发挥作用，影响造血簇、HPC和HSC的形成。Gata2条件性敲除和过表达研究表明，在所有发育阶段，Gata2水平在造血过程中都很重要。尽管先前对表型上富含HPC和HSC的细胞群体的研究显示了Gata2的表达，但在正常造血过程中尚未对表达Gata2的细胞进行直接研究。在本研究中，我们构建了一个Gata2表达不受干扰的Gata2Venus报告基因小鼠模型，以研究表达Gata2和不表达Gata2的细胞的造血功能和转录组。我们发现所有的HSC都表达Gata2。然而，并非主动脉、卵黄动脉、脐动脉和胎肝中的所有HPC都需要或表达Gata2。与依赖Gata2的HPC相比，这些不依赖Gata2的HPC表现出不同的功能输出和基因程序，包括Ras和环磷酸腺苷反应元件结合蛋白途径以及其他Gata因子。我们的结果表明，Gata2在决定HSC命运方面至关重要，但并非在所有具有HPC命运的细胞中都如此，这对当前的重编程策略具有启示意义。
