Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress.

ABSTRACT:

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-7R? chain, which was associated with decreased proliferation and increased apoptosis. Modulating oxidative stress in vitro suggested that oxidative stress selectively leads to decreased IL-7R? expression, and inhibits the survival of IL-7R?-expressing hematopoietic progenitors, potentially linking increased reactive oxygen species and immunopathology.

Innovation

The study results identify a link between oxidative stress and diminished IL-7R? expression and function. Further, the data suggest that this decrease in IL-7R? 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.

SUBMITTER: Lorenzo LP 

PROVIDER: S-EPMC3166202 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature