The Ah receptor in stem cell cycling, regulation, and quiescence

Abstract

Processes that regulate quiescence, self-renewal, and senescence of hematopoietic stem cells (HSCs) are not well understood. Due in part to the ability of xenobiotic ligands to have persistent effects on the immune system in experimental animals, there has been much work to define a physiological role of the aryl hydrocarbon receptor (AhR) and relationships to human disease. Persistent AhR activation by dioxin, a potent agonist, results in altered numbers and function of HSCs in mice. HSCs from AhR null-allele (KO) mice are hyperproliferative and have altered cell cycle. Aging KO mice show characteristics consistent with premature bone marrow exhaustion. We propose that the increased proliferation of HSCs lacking AhR expression or activity is a result of loss of quiescence, and as such, AhR normally acts as a negative regulator to curb excessive or unnecessary proliferation. Similarly, prolonged and/or inappropriate stimulation of AhR activity may compromise the ability of HSCs to sense environmental signals that allow these cells to balance quiescence, proliferation, migration, and differentiation. These data, and others, support a hypothesis that deregulation of AhR function has an important role in HSC regulation and in the etiology and/or progression of certain hematopoietic diseases, many of which are associated with aging.

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

“…Results from a variety of laboratories over the past decade have revealed that the AHR has key roles in the development of cardiovascular, reproductive, and neural systems as well as in hematopoiesis and regulation of immune responses (Benedict, Lin, Loeffler, Peterson, & Flaws, 2000; Esser & Rannug, 2015; Gasiewicz, Singh, & Bennett, 2014; Kimura, Ding, & Tohyama, 2016; Lahvis et al., 2005; Quintana & Sherr, 2013; Singh et al., 2014; Stockinger, Di Meglio, Gialitakis, & Duarte, 2014). Some of these functions may involve natural or endogenous ligands such as metabolites generated by the microbiome, tryptophan metabolites, or lipid‐derived molecules (Bessede et al., 2014; Hubbard, Murray, & Perdew, 2015; McMillan & Bradfield, 2007; Moura‐Alves et al., 2014).…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…This suggests that it has a fundamental role in cellular physiology. In addition, several results from studies with AhR knockout mice have demonstrated functions that need the AhR under developmental stages and for physiologic homeostasis processes without exogenously administered ligands (Gasiewicz et al, 2014).…”

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).…”