Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress.
Animals, Bone Marrow Cells, Disease Models, Animal, Down Syndrome, Female, Hematopoietic Stem Cells, Lymphoid Progenitor Cells, Male, Mice, Mice, Mutant Strains, Oxidative Stress, Reactive Oxygen Species, Receptors, Interleukin-7
Antioxid Redox Signal 2011 Oct 15; 15(8):2083-94.
AIMS: Down Syndrome (DS), a genetic disease caused by a triplication of chromosome 21, is characterized by increased markers of oxidative stress. In addition to cognitive defects, patients with DS also display hematologic disorders and increased incidence of infections and leukemia. Using the Ts65Dn mouse model of DS, the goal of this study was to examine hematopoietic stem and lymphoid progenitor cell function in DS.
RESULTS: Analysis of hematopoietic progenitor populations showed that Ts65Dn mice possessed fewer functional hematopoietic stem cells and a significantly decreased percentage of bone marrow lymphoid progenitors. Increased reactive oxygen species and markers of oxidative stress were detected in hematopoietic stem cell populations and were associated with a loss of quiescence. Bone marrow progenitor populations expressed diminished levels of the IL-7Rα chain, which was associated with decreased proliferation and increased apoptosis. Modulating oxidative stress in vitro suggested that oxidative stress selectively leads to decreased IL-7Rα expression, and inhibits the survival of IL-7Rα-expressing hematopoietic progenitors, potentially linking increased reactive oxygen species and immunopathology.
INNOVATION: The study results identify a link between oxidative stress and diminished IL-7Rα expression and function. Further, the data suggest that this decrease in IL-7Rα is associated with defective hematopoietic development in Down Syndrome.
CONCLUSION: The data suggest that hematopoietic stem and lymphoid progenitor cell defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signaling may alter hematologic development in Ts65Dn mice.
Lorenzo, Laureanne Pilar E; Chen, Haiyan; Shatynski, Kristen E; Clark, Sarah; Yuan, Rong; Harrison, David E; Yarowsky, Paul J; and Williams, Mark S, "Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress." (2011). Faculty Research 2011. 178.