Aryl Hydrocarbon Receptor-Null Allele Mice Have Hematopoietic Stem/Progenitor Cells with Abnormal Characteristics and Functions

Abstract

The aryl hydrocarbon receptor (AhR) belongs to the basic helix-loop-helix family of DNA-binding proteins that play a role in the toxicity and carcinogenicity of certain chemicals. The most potent ligand of the AhR known is 2,3,7,8-tetracholorodibenzo-p-dioxin. We previously reported tetrachlorodibenzo-p-dioxin-induced alterations in numbers and function of hematopoietic stem cells (HSCs). To better understand a possible role of the AhR in hematopoiesis, studies were undertaken in young adult AhR null-allele (KO) mice. These mice have enlarged spleens with increased number of cells from different lineages. Altered expression of several chemokine, cytokine, and their receptor genes were observed in spleen. The KO mice have altered numbers of circulating red and white blood cells, as well as a circadian rhythm-associated 2-fold increase in the number of HSC-enrichedPrimary cultures of KO HSCs and in vivo bromodeoxyuridine incorporation studies demonstrated an approximate 2-fold increased proliferative ability of these cells. More LSK cells from KO mice were in G 1 and S phases of cell cycle. Competitive repopulation studies also indicated significant functional changes in KO HSCs. LSK cells showed increased expression of Cebpe and decreased expression of several hematopoiesis-associated genes. These data indicate that AhR has a physiological and functional role in hematopoiesis. The AhR appears to play a role in maintaining the normal quiescence of HSCs.

The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation

“…These analyses suggested that the AhR plays an important role in blood cell development and were consistent with previous studies. 22,23,26,44 In our studies, we have found that the use of a nontoxic AhR agonist in a directed differentiation scheme dramatically increases the number of HPs and resultant cells. This finding is important in that, traditionally, the evolutionarily conserved AhR has been studied for its role in environmental chemical-induced toxicity, and in our system it is shown to be involved in the growth and the differentiation of at least 2 crucial blood cell types.…”

“…[5][6][7][8][9][10]21 Importantly, recent breakthrough studies suggest that the AhR plays a critical role in nominal hematopoietic stem cell (HSC) growth and differentiation. 22,23 For example, AhR 2/2 mice are characterized by an increased number of bone marrow HSCs 22 and a commensurate increased propensity to develop lymphomas. 24 These insights led to the hypothesis that the AhR, activated by endogenous ligands, regulates stem cell growth and/or differentiation.…”

“…Involvement of the AhR in this process is suggested by decreased numbers of erythrocytes and platelets in young AhR 2/2 mice and the skewing of the blood cell repertoire toward myeloid and B lineage cells as AhR 2/2 mice age. 22,26,27 The differentiation of HSCs into all 8 blood cell lineages is a critical and tightly regulated physiological process. 28 Disruption of this regulation can have a profound downstream effect on multiple hematopoietic cell types, potentially leading to a myriad of blood cell disorders ranging from leukemia to stem cell exhaustion.…”

“…28 Disruption of this regulation can have a profound downstream effect on multiple hematopoietic cell types, potentially leading to a myriad of blood cell disorders ranging from leukemia to stem cell exhaustion. 22,29 However, definition of the molecular mechanisms that control specification of primary human blood cells has been hampered by the lack of a model system in which sufficient numbers of stem or progenitor cells can be grown and the absence of practical and efficient techniques for directing differentiation of hematologic progenitors into end-stage cells. For example, several teams have published proof-of-principle examples of the derivation of megakaryocyte- [30][31][32] and erythroid-lineage cells 30,32,33 from embryonic stem cells and induced pluripotent stem cells (iPSCs).…”

Aryl hydrocarbon receptor–dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets

“…26 In addition to platelets, altered red and leukocyte cell counts have also been observed in AhR KO mice. 27 Therefore, AhR likely impacts many hematopoietic stages and lineages and answers on its specific role in megakaryopoiesis might require a tissue-restricted KO approach.…”