Aryl hydrocarbon receptor-null allele mice have hematopoietic stem/progenitor cells with abnormal characteristics and functions

• Published in: Stem cells and development Vol. 20; no. 5; p. 769
• Main Authors: Singh, Kameshwar P, Garrett, Russell W, Casado, Fanny L, Gasiewicz, Thomas A
• Format: Journal Article
• Language: English
• Published: United States 01.05.2011
• Subjects: Alleles; Animals; Basic Helix-Loop-Helix Transcription Factors - deficiency; Basic Helix-Loop-Helix Transcription Factors - genetics; Bone Marrow - metabolism; Bone Marrow - pathology; Bromodeoxyuridine - analysis; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Count; Cell Cycle - genetics; Cell Proliferation; Circadian Rhythm - genetics; Erythrocytes - pathology; Female; Gene Expression; Hematopoiesis; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Leukocytes - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Aryl Hydrocarbon - deficiency; Receptors, Aryl Hydrocarbon - genetics; Up-Regulation
• ISSN: 1557-8534
• DOI: 10.1089/scd.2010.0333

The aryl hydrocarbon receptor (AhR) belongs to the basic helix-loop-helix family of DNA-binding proteins that play a role in the toxicity and carcinogenicity of certain chemicals. The most potent ligand of the AhR known is 2,3,7,8-tetracholorodibenzo-p-dioxin. We previously reported tetrachlorodibenzo-p-dioxin-induced alterations in numbers and function of hematopoietic stem cells (HSCs). To better understand a possible role of the AhR in hematopoiesis, studies were undertaken in young adult AhR null-allele (KO) mice. 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. The KO mice have altered numbers of circulating red and white blood cells, as well as a circadian rhythm-associated 2-fold increase in the number of HSC-enriched Lin(-)Sca-1(+)c-Kit(+) (LSK) cells in bone marrow. Primary cultures of KO HSCs and in vivo bromodeoxyuridine incorporation studies demonstrated an approximate 2-fold increased proliferative ability of these cells. More LSK cells from KO mice were in G(1) and S phases of cell cycle. Competitive repopulation studies also indicated significant functional changes in KO HSCs. LSK cells showed increased expression of Cebpe and decreased expression of several hematopoiesis-associated genes. These data indicate that AhR has a physiological and functional role in hematopoiesis. The AhR appears to play a role in maintaining the normal quiescence of HSCs.