Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into all blood lineages. A balance among quiescence, self-renewal, proliferation, and differentiation is precisely maintained to preserve multi-lineage generation throughout the organism's lifetime, and during responses to stress, tissue damage, and pathogens. Although the dysregulation of these processes in HSCs has immense implications for human health, how this balance is regulated is not well understood. Recent data support the novel hypothesis that the aryl hydrocarbon receptor (AHR), a bHLH transcription factor, is a physiological regulator of HSCs. These data support the contention that AHR acts as a negative regulator by curbing excessive or unnecessary proliferation and promoting HSC quiescence. These data also support an overall hypothesis that AHR dysregulation, and thus disruption of the quiescence-proliferation balance, through xenobiotic/chemotherapeutic exposure or genetic/epigenetic events, has an important role in the etiology and progression of hematopoietic disease. Much data also indicates that the regulation of AHR expression is a key rate-limiting element controlling downstream AHR signaling events in HSCs. Yet, virtually nothing is known about how this occurs or the identity of signals from HSCs or other cells that regulate this process. Here we will test the hypothesis that Ahr gene expression is regulated by HSC-intrinsic and -extrinsic factors, and this regulation is essential for the balance between HSC quiescence and proliferation. Using a combination of molecular and cell biology techniques and unique animal models, we will determine 1) if the presence of the AHR in bone marrow niche cells has a role in the regulation of Ahr expression in HSCs and/or control of HSC function, 2) if the down- regulation of Ahr is absolutely necessary for HSC to transit from quiescence to proliferation, and 3) the mechanism(s) responsible for Ahr down-regulation.
Understanding what regulates the incredible regenerative capacity of hematopoietic stem cells (HSCs) has wide clinical implications for bone marrow transplantation, bone marrow failure associated with anti-cancer treatment, the development of hematopoietic cancers, and the normal response to pathogens. We hypothesize that the aryl hydrocarbon receptor (AHR) signaling pathway is an important factor in HSCs by regulating the balance between quiescence and proliferation, and that expression of the AHR gene is a key event in this regulation. Furthermore, we envision that the dysregulation of AHR expression/activity by xenobiotic exposure or genetic/epigenetic events plays a significant role in the generation of leukemia or other hematopoietic disorders. These studies will substantially enhance the understanding of AHR and stem cell biology, the processes of aging, tissue regeneration, and hematopoietic disease, as well as our ability to manipulate HSCs and possibly other stem cell populations for therapeutic purposes. Thus, the potential human health significance and impact are high.
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