The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation
The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation
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DOI：
10.1182/blood-2012-11-466722
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发表时间：
2013-07-18
期刊：
影响因子：
20.3
通讯作者：
Murphy, George J.
中科院分区：
文献类型：
--
作者：
Smith, Brenden W.;Rozelle, Sarah S.;Murphy, George J.
进化上保守的芳基烃受体（AhR）因其在环境化学品引起的毒性中的作用而被研究。然而，最近的研究表明，AhR 可能以细胞特异性的方式调节发育过程中的造血和免疫系统。这些结果，加上缺乏能够产生大量能够分化为巨核细胞和红系细胞的原代人类造血祖细胞（HP）的体外模型系统，促使我们确定 AhR 调节是否可以促进祖细胞扩增以及巨核细胞和红系细胞分化。使用一种新型的、基于多能干细胞、化学成分明确、无血清和饲养细胞的培养系统，我们发现 AhR 在 HP 中表达，并且值得注意的是，AhR 激活驱动 HP、巨核细胞谱系细胞和红系谱系细胞前所未有的扩增。快速扩张的祖细胞群中的进一步 AhR 调节指导细胞命运，慢性 AhR 激动允许红细胞分化，而急性拮抗则有利于巨核细胞分化。这些结果强调了新的符合良好生产规范的平台的开发，该平台可产生几乎无限数量的人类 HP，用于检查红细胞和血小板的发育，包括评估造血过程中 AhR 关键细胞命运决策的作用。
The evolutionarily conserved aryl hydrocarbon receptor (AhR) has been studied for its role in environmental chemical-induced toxicity. However, recent studies have demonstrated that the AhR may regulate the hematopoietic and immune systems during development in a cell-specific manner. These results, together with the absence of an in vitro model system enabling production of large numbers of primary human hematopoietic progenitor cells (HPs) capable of differentiating into megakaryocyte- and erythroid-lineage cells, motivated us to determine if AhR modulation could facilitate both progenitor cell expansion and megakaryocyte and erythroid cell differentiation. Using a novel, pluripotent stem cell-based, chemically-defined, serum and feeder cell-free culture system, we show that the AhR is expressed in HPs and that, remarkably, AhR activation drives an unprecedented expansion of HPs, megakaryocyte-lineage cells, and erythroid-lineage cells. Further AhR modulation within rapidly expanding progenitor cell populations directs cell fate, with chronic AhR agonism permissive to erythroid differentiation and acute antagonism favoring megakaryocyte specification. These results highlight the development of a new Good Manufacturing Practice-compliant platform for generating virtually unlimited numbers of human HPs with which to scrutinize red blood cell and platelet development, including the assessment of the role of the AhR critical cell fate decisions during hematopoiesis.