Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBPα
Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBPα
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DOI：
10.1038/sj.emboj.7601199
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发表时间：
2006-07-26
期刊：
影响因子：
11.4
通讯作者：
Nakajima, Hideaki
中科院分区：
文献类型：
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作者：
Fukuchi, Yumi;Shibata, Fumi;Nakajima, Hideaki
CCAAT/增强子结合蛋白（C/EBP）a是早期髓样分化的关键调节因子。尽管C/EBP α已显示将B细胞转化为髓系，但C/EBP α在各种造血祖细胞和干细胞中的确切作用仍然不清楚。为了研究C/EBP α在各种祖细胞中激活的结果，并详细说明谱系转换的潜在机制，我们建立了表达C/EBP α条件形式的转基因小鼠。使用这些小鼠，我们表明，巨核细胞/红系祖细胞（MEP）和共同的淋巴祖细胞（CLP）可以在体外通过短期激活C/EBP α重定向为功能性巨噬细胞，并通过双表型中间细胞克隆发生转换。此外，小鼠体内C/EBP α的激活导致成熟粒细胞和髓系祖细胞增加，同时造血干细胞和非髓系祖细胞减少。我们的研究表明，C/EBP α可以激活MEP和CLP的潜在髓样分化程序，并表明其整体激活影响体内多谱系稳态。
CCAAT/enhancer-binding protein (C/EBP) a is a critical regulator for early myeloid differentiation. Although C/EBP alpha has been shown to convert B cells into myeloid lineage, precise roles of C/EBP alpha in various hematopoietic progenitors and stem cells still remain obscure. To examine the consequence of C/EBP alpha activation in various progenitors and to address the underlying mechanism of lineage conversion in detail, we established transgenic mice expressing a conditional form of C/EBP alpha. Using these mice, we show that megakaryocyte/erythroid progenitors (MEPs) and common lymphoid progenitors (CLPs) could be redirected to functional macrophages in vitro by a short-term activation of C/EBP alpha, and the conversion occurred clonally through biphenotypic intermediate cells. Moreover, in vivo activation of C/EBP alpha in mice led to the increase of mature granulocytes and myeloid progenitors with a concomitant decrease of hematopoietic stem cells and nonmyeloid progenitors. Our study reveals that C/EBP alpha can activate the latent myeloid differentiation program of MEP and CLP and shows that its global activation affects multilineage homeostasis in vivo.