Section of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Blood. 2013 Jul 18;122(3):376-85. doi: 10.1182/blood-2012-11-466722. Epub 2013 May 30.
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.
进化保守的芳香烃受体（AhR）已被研究其在环境化学诱导的毒性中的作用。然而，最近的研究表明，AhR 可能以细胞特异性的方式调节造血和免疫系统的发育。这些结果，再加上缺乏能够产生大量能够分化为巨核细胞和红细胞谱系细胞的原代人造血祖细胞（HPs）的体外模型系统，促使我们确定 AhR 调节是否能够促进祖细胞的扩增以及巨核细胞和红细胞的分化。使用新型、多能干细胞为基础的、化学定义的、无血清和无饲养细胞的培养系统，我们表明 AhR 在 HPs 中表达，并且令人惊讶的是，AhR 激活驱动 HPs、巨核细胞谱系细胞和红细胞谱系细胞的空前扩增。在快速扩增的祖细胞群体中进一步的 AhR 调节指导细胞命运，慢性 AhR 激动剂允许红细胞分化，急性拮抗剂有利于巨核细胞的特化。这些结果突出了一种新的符合良好生产规范的平台的发展，该平台可生成数量几乎无限的人类 HPs，用于仔细研究红细胞和血小板的发育，包括评估 AhR 在造血过程中对关键细胞命运决定的作用。
