Granulopoiesis requires increased C/EBPα compared to monopoiesis, correlated with elevated Cebpa in immature G-CSF receptor versus M-CSF receptor expressing cells.
Granulopoiesis requires increased C/EBPα compared to monopoiesis, correlated with elevated Cebpa in immature G-CSF receptor versus M-CSF receptor expressing cells.
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DOI：
10.1371/journal.pone.0095784
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Friedman AD
中科院分区：
文献类型：
--
作者：
Ma O;Hong S;Guo H;Ghiaur G;Friedman AD
C/eBPα是粒细胞-单核细胞祖细胞形成所必需的；然而，它在随后的髓系谱系规范中的作用仍不确定。用两种CEBPA shRNAs转导小鼠骨髓，可显著增加单核细胞数，减少甲基纤维素粒细胞集落或液体培养中单核细胞与中性粒细胞的比率。在骨髓shRNA转导和移植以及CEBPA基因敲除的人骨髓CD34+细胞中也发现了类似的结果。这些结果显然反映了髓系特征的改变，因为类似的敲除允许几乎完全的32DCl3粒细胞成熟。CEBPA基因敲除也产生了谱系阴性的原始细胞，其克隆复制能力增加，但细胞周期参数没有变化，可能反映了完全的分化阻断。对谱系偏斜影响最大的shRNA使CEBPA在分化细胞中减少3倍，而在积累原始细胞方面减少6倍。提示CEBPA是相关的shRNA靶点，shRNA耐药的C/EBPα-ER挽救了骨髓的造血。CEBPA在小鼠骨髓细胞中的基因敲除也增加了体外红细胞生成，可能反映了PU1减少1.6倍导致GATA-1去抑制。对CEBPA基因敲除后积累的谱系阴性母细胞的全球基因表达分析表明，已知的粒细胞生成转录调节因子CEBPE和Gfi1减少，Ets1和Klf5也减少。通过将LIN−Sca-1−c-Kit+细胞分为GCSFR+MCSFR−或GCSFR−MCSFR+亚群，分离出富含未成熟粒细胞或单核细胞祖细胞/前体的群体。C-Kit+GCSFR+组和c-Kit+MCSFR+组的CEBPA、CEBPE、Gfi1、Ets1和Klf5基因表达增加，PU.1水平相近。综上所述，粒细胞需要较高水平的C/EBPCEBPA，而单核细胞则需要较低水平的α，与单核细胞祖细胞相比，粒细胞中CEBPA基因表达的增加可能促进了这种髓系分化。
C/EBPα is required for the formation of granulocyte-monocyte progenitors; however, its role in subsequent myeloid lineage specification remains uncertain. Transduction of murine marrow with either of two Cebpa shRNAs markedly increases monocyte and reduces granulocyte colonies in methylcellulose or the monocyte to neutrophil ratio in liquid culture. Similar findings were found after marrow shRNA transduction and transplantation and with CEBPA knockdown in human marrow CD34+ cells. These results apparently reflect altered myeloid lineage specification, as similar knockdown allowed nearly complete 32Dcl3 granulocytic maturation. Cebpa knockdown also generated lineage-negative blasts with increased colony replating capacity but unchanged cell cycle parameters, likely reflecting complete differentiation block. The shRNA having the greatest effect on lineage skewing reduced Cebpa 3-fold in differentiating cells but 6-fold in accumulating blasts. Indicating that Cebpa is the relevant shRNA target, shRNA-resistant C/EBPα-ER rescued marrow myelopoiesis. Cebpa knockdown in murine marrow cells also increased in vitro erythropoiesis, perhaps reflecting 1.6-fold reduction in PU.1 leading to GATA-1 derepression. Global gene expression analysis of lineage-negative blasts that accumulate after Cebpa knockdown demonstrated reduction in Cebpe and Gfi1, known transcriptional regulators of granulopoiesis, and also reduced Ets1 and Klf5. Populations enriched for immature granulocyte or monocyte progenitor/precursors were isolated by sorting Lin−Sca-1−c-Kit+ cells into GCSFR+MCSFR− or GCSFR−MCSFR+ subsets. Cebpa, Cebpe, Gfi1, Ets1, and Klf5 RNAs were increased in the c-Kit+GCSFR+ and Klf4 and Irf8 in the c-Kit+MCSFR+ populations, with PU.1 levels similar in both. In summary, higher levels of C/EBPα are required for granulocyte and lower levels for monocyte lineage specification, and this myeloid bifurcation may be facilitated by increased Cebpa gene expression in granulocyte compared with monocyte progenitors.
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影响因子：
11.2
作者：
Lidonnici MR;Audia A;Soliera AR;Prisco M;Ferrari-Amorotti G;Waldron T;Donato N;Zhang Y;Martinez RV;Holyoake TL;Calabretta B
通讯作者：
Calabretta B
影响因子：
2.7
作者：
Humbert, Magali;Halter, Veronika;Tschan, Mario P.
通讯作者：
Tschan, Mario P.
DOI：
10.1084/jem.20050075
发表时间：
2005-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dakic A;Metcalf D;Di Rago L;Mifsud S;Wu L;Nutt SL
通讯作者：
Nutt SL
影响因子：
5.2
作者：
Paz-Priel, I;Cai, DH;Friedman, AD
通讯作者：
Friedman, AD
影响因子：
5.3
作者：
Radomska, HS;Huettner, CS;Tenen, DG
通讯作者：
Tenen, DG