Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice
Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice
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DOI：
10.1182/blood-2011-10-386359
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发表时间：
2012-05-17
期刊：
影响因子：
20.3
通讯作者：
Erkeland, Stefan J.
中科院分区：
文献类型：
--
作者：
Alemdehy, Mir Farshid;van Boxtel, Nicole G. J. A.;Erkeland, Stefan J.
MicroRNAs(MiRNAs)具有调节细胞分化程序的潜力；然而，原代造血干细胞(HSCs)中的miRNA缺陷导致小鼠HSC耗尽，使得miRNAs是否在早期谱系决定中发挥作用的问题尚未得到回答。为了解决这个问题，我们在体内CCAAT/增强子结合蛋白α(C/EBPA)阳性的髓系祖细胞中删除了Dicer1，它编码miRNA生物发生所必需的RNaseIII酶。与在HSCs中的结果相反，我们发现miRNA缺失既不影响髓系祖细胞的数量，也不影响C/EBPA阳性祖细胞的百分比。对野生型和Dicer1缺陷型粒细胞-巨噬细胞祖细胞(GMPs)的基因表达谱分析显示，GMPs中有20个miRNA家族活跃。在Dicer1缺失的GMP中去抑制的miRNA靶标中，27%通常只在HSC中表达，或者是针对多能祖细胞和红细胞生成的，这表明基因表达格局发生了变化。DICER1缺陷的GMP在体外的髓系发育中存在缺陷，并表现出增强的复制能力，表明这些细胞重新获得了自我更新的潜力。在小鼠中，Dicer1缺失阻碍了单核细胞的分化，耗尽了巨噬细胞，并导致了具有Pelger-Huet异常形态特征的髓系发育不良。这些结果为GMP的自我更新和向髓系分化的细胞程序提供了miRNA控制的开关的证据。(血。2012年；119(20)：4723-4730)
MicroRNAs (miRNAs) have the potential to regulate cellular differentiation programs; however, miRNA deficiency in primary hematopoietic stem cells (HSCs) results in HSC depletion in mice, leaving the question of whether miRNAs play a role in early-lineage decisions unanswered. To address this issue, we deleted Dicer1, which encodes an essential RNase III enzyme for miRNA biogenesis, in murine CCAAT/enhancer-binding protein alpha (C/EBPA)-positive myeloid-committed progenitors in vivo. In contrast to the results in HSCs, we found that miRNA depletion affected neither the number of myeloid progenitors nor the percentage of C/EBPA-positive progenitor cells. Analysis of gene-expression profiles from wild-type and Dicer1-deficient granulocyte-macrophage progenitors (GMPs) revealed that 20 miRNA families were active in GMPs. Of the derepressed miRNA targets in Dicer1-null GMPs, 27% are normally exclusively expressed in HSCs or are specific for multipotent progenitors and erythropoiesis, indicating an altered gene-expression landscape. Dicer1-deficient GMPs were defective in myeloid development in vitro and exhibited an increased replating capacity, indicating the regained self-renewal potential of these cells. In mice, Dicer1 deletion blocked monocytic differentiation, depleted macrophages, and caused myeloid dysplasia with morphologic features of Pelger-Huet anomaly. These results provide evidence for a miRNA-controlled switch for a cellular program of self-renewal and expansion toward myeloid differentiation in GMPs. (Blood. 2012; 119(20):4723-4730)