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The aryl hydrocarbon receptor modulates murine hematopoietic stem cell homeostasis and influences lineage-biased stem and progenitor cells.

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 towards specific lineage-biased progenitors is not well understood. Our current study revealed that AHR-KO mice have an increased proportion of myeloid-biased HSCs and myeloid-biased multipotent progenitors (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 pre-granulocyte/monocyte 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 are 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. Additionally, the data presented provide potential insight into how deliberate modulation of AHR signaling could help with the treatment of a broad ranges of diseases that require the hematopoietic compartment.