The core function of hematopoietic stem and progenitor cells (HSPCs) is to provide lifelong production of all lineages of the blood and immune cells. The mechanisms that modulate HSPC homeostasis and lineage biasing are not fully understood. Growing evidence implicates the aryl hydrocarbon receptor (AHR), an environment-sensing transcription factor, as a regulator of hematopoiesis. AHR ligands modulate the frequency of mature hematopoietic cells in the bone marrow and periphery, while HSPCs from mice lacking AHR (AHR KO) have increased proliferation. Yet, whether AHR modulates HSPC lineage potential and directs differentiation toward specific lineage-biased progenitors is not well understood. This study revealed that AHR KO mice have an increased proportion of myeloid-biased HSCs and myeloid-biased multipotent progenitor (MPP3) cells. Utilizing inducible AHR knockout mice (iAHR KO), it was discovered that acute deletion of AHR doubled the number of MPP3 cells and altered the composition of downstream lineage-committed progenitors, such as increased frequency of pregranulocyte/premonocyte committed progenitors. Furthermore, in vivo antagonism of the AHR led to a 2.5-fold increase in the number of MPP3 cells and promoted myeloid-biased differentiation. Using hematopoietic-specific conditional AHR knockout mice (AHRVav1) revealed that increased frequency of myeloid-biased HSCs and myeloid-biased progenitors is driven by AHR signaling that is intrinsic to the hematopoietic compartment. These findings demonstrate that the AHR plays a pivotal role in regulating steady-state hematopoiesis, influencing HSPC homeostasis and lineage potential. In addition, the data presented provide potential insight into how deliberate modulation of AHR signaling could help with the treatment of a broad range of diseases that require the hematopoietic compartment.

中文翻译：

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芳基烃受体调节小鼠造血干细胞稳态并影响谱系偏向干细胞和祖细胞


造血干细胞和祖细胞 (HSPC) 的核心功能是终身生成所有谱系的血液和免疫细胞。调节 HSPC 稳态和谱系偏向的机制尚不完全清楚。越来越多的证据表明芳烃受体（AHR）（一种环境感知转录因子）是造血的调节因子。 AHR 配体调节骨髓和外周成熟造血细胞的频率，而缺乏 AHR (AHR KO) 的小鼠的 HSPC 增殖增加。然而，AHR 是否调节 HSPC 谱系潜力并指导向特定谱系偏向的祖细胞分化尚不清楚。这项研究表明，AHR KO 小鼠的髓系造血干细胞和髓系多能祖细胞 (MPP3) 的比例增加。利用诱导型 AHR 敲除小鼠 (iAHR KO)，发现 AHR 的急性缺失使 MPP3 细胞数量增加一倍，并改变下游谱系定型祖细胞的组成，例如前粒细胞/前单核细胞定型祖细胞的频率增加。此外，AHR 的体内拮抗作用导致 MPP3 细胞数量增加 2.5 倍，并促进骨髓偏向分化。使用造血特异性条件性 AHR 基因敲除小鼠 (AHRVav1) 发现，造血室固有的 AHR 信号传导驱动了髓系造血干细胞和髓系祖细胞频率的增加。这些发现表明 AHR 在调节稳态造血、影响 HSPC 稳态和谱系潜力方面发挥着关键作用。 此外，所提供的数据还为了解 AHR 信号传导的有意调节如何帮助治疗需要造血室的多种疾病提供了潜在的见解。