The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations

Abstract

The aryl hydrocarbon receptor (AhR) is known mainly as the mediator for the toxicity of certain xenobiotics. However, there is also much information to indicate that this transcription factor has important biological functions. Here we review the evidence that the AhR has a significant role in the regulation of hematopoietic stem cells (HSCs). Data to support this come from studies with xenobiotic AhR ligands, phenotypic analyses of mice lacking AhR, examining the presence and regulation of the AhR within HSCs, knowledge of genes and signaling pathways regulated by the AhR, and investigations of hematopoietic disorders. Based on this information, we hypothesize that AhR expression is necessary for the proper maintenance of quiescence in HSCs, and that AhR down-regulation is essential for "escape" from quiescence and subsequent proliferation of these cells. This implicates the AhR as a negative regulator of hematopoiesis with a function of curbing excessive or unnecessary proliferation. This provides an important advantage by preventing the premature exhaustion of HSCs and sensitivity to genetic alterations, thus preserving HSC function and long-term multi-lineage generation over the lifespan of the organism. This also implicates a role of the AhR in aging processes. AhR dysregulation may result in the altered ability of HSCs to sense appropriate signals in the bone marrow microenvironment leading to hematopoietic disease. It is also reasonable to hypothesize that this protein has an important function in the regulation of other tissue stem cell populations. Suggestive evidence is consistent with a role in skin and neural stem cells.

Fig. 1

Simplified classic schematic of hematopoiesis indicating the cell surface markers expressed at different stages of differentiation. Broken lines indicate the recently proposed revision to this classical model where a myeloid based model of hematopoiesis has been suggested [97].

Fig. 2

TCDD inhibits steps leading to repopulation of the bone marrow (BM) after transplantation. A, Competitive repopulation of recipients evaluates the ability of HSCs from TCDD- or vehicle-treated CD45.2⁺ donor mice to reconstitute the BM of irradiated recipient CD45.1⁺ animals in the presence of competitive donor (CD45.1⁺) HSCs. The percentages and phenotypic composition of CD45.2⁺ cells in the reconstituted recipient are analyzed. B, TCDD treatment alters HSCs to prevent successful repopulation of the BM. Repopulation requires HSC to migrate from the circulation through endothelial cells of the BM sinusoids into the BM. Once in the BM, HSC must be retained and engrafted or they will be mobilized back into circulation to find other niches to populate.

Fig. 3

Simplified model of AhR regulation of HSCs. A, The AhR-ligand TCDD binds to AhR which translocates to the nucleus and mediates genetic/epigenetic regulation, HSC-niche interactions, and alterations of different end-points. B, In AhR^−/− mice, the HSCs are constitutively in a higher cycling status that corresponds with a larger HSC pool size.