Aryl hydrocarbon receptor (AhR) belongs to the basic helix-loop helix family of DNA- binding proteins. AhR sense molecules and stimuli from cellular environment and initiate signaling cascades to elicit appropriate cellular responses. Though it binds to a diverse group of environmental chemicals, food and food products, the most potent AhR ligand known is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure produces a wide range of biological effects in animals. Increased incidences of leukemia and lymphoma have been reported in human populations exposed to TCDD and other related environmental chemicals. TCDD is classified as human carcinogen by IARC.
Although AhR activation by TCDD has been known for its effects on the various physiological functions, studies on the role of AhR in hematopoietic stem cells functions are lacking. Hematopoietic stem cells (HSCs) are responsible for maintaining homeostasis of blood cells by differentiating to hematopoietic progenitor cells and ultimately to mature immune system lineage cells. They also self-renew to keep a constant pool of HSCs. Premitive HSCs are highly sensitive to environmental chemical insults that produce aberrant changes in differentiation and proliferation leading to development of hematopoietic diseases.
CURRENT RESEARCH AREAS
1. Does Aryl hydrocarbon receptor activation induce changes in hematopoietic stem cell functions?
Our laboratory has reported that activation of AhR by its ligand TCDD produces time dependent decrease in B-cells and increase in myeloid populations in experimental mouse model. TCDD exposed HSCs have lower colony forming ability and exhibited diminished capacity to reconstitute and home in the bone marrow (BM) of irradiated recipients. TCDD treatment to mice increased the numbers of phenotypically defined HSCs in BM. These HSCs showed altered migration to BM in vivo and to the chemokine CXCL12 in vitro. Also, these cells showed increased expression of receptors CD184 (CXCR4) and CD44, and genes expressing Scin, Nqo1, Flnb, Mmp8, Ilf9, and Slamf7. TCDD also produced alteration in genes envolved in hematological system development and function including Fos, JunB, Egr1, Ptgs2 (Cox2) and Cxcl2 (Singh et al. Carcinogenesis 30: 11-19, 2009; Casado et al. Mol Pharmacol 80: 673-682, 2011).
2. Does Aryl hydrocarbon receptor deficiency produce alteration in primitive hematopoietic stem cells functions?
To further validate our hypothesis that AhR does play a role in hematopoiesis and HSCs functions, we use a AhR-deficient mouse model. These mice have enlarged spleens with increased number of cells from different lineages. Altered expression of several chemokine, cytokine and their receptor genes were observed in spleen. There were changes in the numbers of circulating red, white blood cells and increase in HSC and progenitor cells in BM. The AhR-deficient mice have alterations in HSCs functions and expression of several hematopoiesis associated genes. These data further support our hypothesis that AhR has a physiological and functional role in hematopoiesis and also in maintaining the normal quiescence of HSCs (Singh et al. Stem Cell Develop 20: 769-783, 2011).
3. Does Aryl hydrocarbon deficiency promote early aging and hematopoietic diseases?
In our earlier publication, we have shown that HSCs from AhR-deficient mice have inherent high rates of cell division. We hypothesized that AhR is a negative regulator of HSCs proliferation by promoting these cells to remain in quiescence. We further hypothesize that since AhR-deficient mice have hyperproliferating HSCs, these mice may develop premature HSCs exhaustion and may show early sign of aging and/or aberrant changes in hyperproliferating HSCs leading to hematologic diseases. Our preliminary studies show that AhR-deficient aging mice do indeed show sign of HSCs exhaustion, increase early mortality and aberrant HSCs functions.
Gasiewicz TA, Singh KP, Bennett JA. "The Ah receptor in stem cell cycling, regulation, and quiescence." Annals of the New York Academy of Sciences. 2014 Mar; 1310:44-50. Epub 2014 Feb 03.
2014 Jan 15
Singh KP, Bennett JA, Casado FL, Walrath JL, Welle SL, Gasiewicz TA. "Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice." Stem cells and development. 2014 Jan 15; 23(2):95-106. Epub 2013 Oct 19.
Casado FL, Singh KP, Gasiewicz TA. "Aryl hydrocarbon receptor activation in hematopoietic stem/progenitor cells alters cell function and pathway-specific gene modulation reflecting changes in cellular trafficking and migration." Molecular pharmacology. 2011 Oct; 80(4):673-82. Epub 2011 Jul 26.
Singh KP, Garrett RW, Casado FL, Gasiewicz TA. "Aryl hydrocarbon receptor-null allele mice have hematopoietic stem/progenitor cells with abnormal characteristics and functions." Stem cells and development. 2011 May; 20(5):769-84. Epub 2010 Nov 09.
Casado, F.L.; Singh, K.P.; Gasiewicz, T.A. "The aryl hydrocarbon receptor: Regulation of hematopoiesis and involvement in the progression of blood diseases." Blood Cell Mol. Dis. 2010; 44: 199-206.