Aryl Hydrocarbon Receptor Deficiency in an Exon 3 Deletion Mouse Model Promotes Hematopoietic Stem Cell Proliferation and Impacts Endosteal Niche Cells

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to the Per-Arnt-Sim (PAS) family of proteins. The AHR is involved in hematopoietic stem cell (HSC) functions including self-renewal, proliferation, quiescence, and differentiation. We hypothesize that AHR impacts HSC functions by influencing genes that have roles in HSC maintenance and function and that this may occur through regulation of bone marrow (BM) niche cells. We examined BM and niche cells harvested from 8-week-old AHR null-allele (KO) mice in which exon 3 was deleted in the Ahr gene and compared these data to cells from B6 control mice; young and old (10 months) animals were also compared. We report changes in HSCs and peripheral blood cells in mice lacking AHR. Serial transplantation assays revealed a significant increase in long term HSCs. There was a significant increase in mesenchymal stem cells constituting the endosteal BM niche. Gene expression analyses of HSCs revealed an increase in expression of genes involved in proliferation and maintenance of quiescence. Our studies infer that loss of AHR results in increased proliferation and self-renewal of long term HSCs, in part, by influencing the microenvironment in the niche regulating the balance between quiescence and proliferation in HSCs.

Does the aryl hydrocarbon receptor regulate pluripotency?

“…Consistent with this hypothesis, our recent study suggests that Ahr expression must be repressed lest the ES cells would slow down proliferation and lose pluripotency [18, 21]. A similar AHR expression pattern and regulatory function is found in the differentiation of hematopoietic stem cells and cancer stem cells [36-39] suggestive of a widespread AHR function in the ontogeny of diverse stem cell lineages.…”

“…These observations suggest that AHR may control the pluripotent population by disrupting their self-renewal through lengthening mitosis. The same is true in hematopoietic stem cells, where knockout of Ahr or treatment with an AHR antagonist promotes their expansion and proliferation, indicative of the role of AHR in the maintenance of the stem cell pool [38, 39, 45-47]. Unlike in ES cells, however, AHR maintains the hematopoietic stem cell population by restricting their exit from quiescence.…”

Stem Cells, Cancer, and MUSASHI in Blood and Guts

“…As previously described, SR1 does not expand mouse HSCs despite its effect on human and other species 34 . Yet AHR knockout HSCs have enhanced cycling and aged mice develop MDS and exhibit reduced self-renewal 35–37 . Despite efforts to identify unique targets or pathways, MSI2 controls thousands of targets feeding into multiple pathways that are cell context dependent.…”

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options

“…Accumulating evidence in mouse embryonic stem cells and hematopoietic system suggests that AHR is involved in regulation of stem/progenitor cells (Singh et al, 2009;Gasiewicz et al, 2014;Wang et al, 2016;Unnisa et al, 2016). Evidence for stem/progenitor cells as target of human AHR has also been obtained in studies of chloracne, the hallmark of dioxin toxicity (Ju et al, 2011;Bock, 2016).…”