The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration

Abstract

While sensing the cell environment, the aryl hydrocarbon receptor (AHR) interacts with different pathways involved in cellular homeostasis. This review summarizes evidence suggesting that cellular regeneration in the context of aging and diseases can be modulated by AHR signaling on stem cells. New insights connect orphaned observations into AHR interactions with critical signaling pathways such as WNT to propose a role of this ligand-activated transcription factor in the modulation of cellular regeneration by altering pathways that nurture cellular expansion such as changes in the metabolic efficiency rather than by directly altering cell cycling, proliferation, or cell death. Targeting the AHR to promote regeneration might prove to be a useful strategy to avoid unbalanced disruptions of homeostasis that may promote disease and also provide biological rationale for potential regenerative medicine approaches.

Figure 1

Ubiquitous AHR expression in iPSC and HSC regardless of potency and self-renewal activity. (a-b) AHR is expressed in (a) iPSC (OCT3/4+) and (b) cells from iPSC-derived embryoid bodies differentiating into hematopoietic lineages. Blue dots/areas correspond to fluorescence minus one (FMO) gating controls. (c-d) AHR is expressed in mobilized peripheral blood which is known to be enriched for (c) HSC and (d) leukemic cells with abnormal self-renewing activity.

Figure 2

The AHR ligand binding pocket occupied during exposure to toxic xenobiotics such as dioxins (TCDDs) and polychlorinated biphenyls (PCBs) is not likely to accommodate ligands such as SR1, L-kynurenine, or glucose.