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 comes 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 downregulation 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 longterm 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.

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

“…Of great scientific interest is the role that the AhR seems to play in progenitor cell expansion and differentiation in which the Wnt/b-catenin pathway is active (Laiosa et al, 2003;Singh et al, 2009;Boitano et al, 2010;Latchney et al, 2011;Procházková et al, 2011). Furthermore, a role for AhR in tissue regeneration has been described in models of liver, fin, and cardiac tissue regeneration (Mathew et al, 2006;Mitchell et al, 2006;Hofsteen et al, 2013).…”

“…In any case, the strong flexibility of AhR activation by chemicals makes it an attractive pharmacological target, as evident from experiments on stem cell proliferation and inhibition of cancer cells (Safe and McDougal, 2002;Lawrence et al, 2008;Singh et al, 2009;Boitano et al, 2010).…”

The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation

“…24 These insights led to the hypothesis that the AhR, activated by endogenous ligands, regulates stem cell growth and/or differentiation. 25 Despite these early results, little is known about the effects of AhR modulation on the development of megakaryocyte-or erythroid-lineage cells from bipotential progenitors. 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.…”

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

“…The hematopoietic stem cells (HSCs) differentiate into multiple lineages (Singh et al, 2009b). The earliest multipotential progenitor cells (Sca-1 ϩ /c-Kit ϩ ) differentiate into committed lymphoid progenitors (Sca-1 ϩ /c-Kit ϩ low) and myeloid progenitors (Sca-1 Ϫ /c-Kit ϩ ) cells, which proliferate and differentiate to lineage-specific progenitors that are committed to forming either B-lineage lymphocytes (B220 ϩ ) or granulocytes (Gr-1 ϩ ).…”