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-7Ra chain, which was associated with decreased proliferation and increased apoptosis. Modulating oxidative stress in vitro suggested that oxidative stress selectively leads to decreased IL-7Ra expression, and inhibits the survival of IL-7Ra-expressing hematopoietic progenitors, potentially linking increased reactive oxygen species and immunopathology. Innovation: The study results identify a link between oxidative stress and diminished IL-7Ra expression and function. Further, the data suggest that this decrease in IL-7Ra 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. Antioxid. Redox Signal. 15, 2083Signal. 15, -2094

Tumorigenesis in Down's syndrome: big lessons from a small chromosome

“…Age-dependent telomere attrition in neutrophils, B lymphocytes and T lymphocytes is >threefold higher in DS 138 , and the difference in telomere length, relative to euploid controls, is detectable at fetal stage 139 . Adult mouse models of DS have an accelerated stem cell ageing phenotype, defective HSC and lymphoid progenitor cell compartments in the bone marrow, with lower proliferation capability and a higher rate of apoptosis 140 . There are also differences in telomere shortening between tissues: although primary DS leukocytes, HSCs and NSCs lose replicative potential faster than euploid controls 125,138,139 , primary DS skin fibroblasts do not 91 (even though they replicate more slowly).…”

Functional and biochemical characterization of soleus muscle in Down syndrome mice: insight into the muscle dysfunction seen in the human condition

“…Following the determination of L o, the bath temperature was increased to 37°C, and the muscle was allowed to equilibrate for an additional 30 min. The force-frequency relationship was determined using contractions evoked at stimulus frequencies of 1,15,30,50,80,120,160,250, and 300 Hz with train duration of 500 ms with 2 min of recovery between contractions (Grass S48 stimulator; West Warwick, RI). Two minutes following the end of the force-frequency protocol, the muscles underwent a fatigue protocol (40 Hz, 0.5 trains/s, 500 ms trains) for 5 min, followed by a recovery period (40 Hz, 0.5 trains/s, 500-ms trains) with force measurements obtained at 30 s, and 1, 2, 5, 10, and 15 min.…”

“…Furthermore, microarray analyses did not reveal gene expression patterns that would indicate the presence of oxidative stress. The lack of oxidative stress in muscle is surprising, given that other cell types isolated from DS and Ts65Dn tissue demonstrate increased oxidant production and markers of oxidative stress (7,30). One possibility for this discrepancy might be that SOD1 was not elevated in Ts65Dn muscle to a sufficient degree to elevate oxidant production (52).…”

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

“…The development of dementia in DS patients is paralleled with decrease in SOD activity [48]. A report points to increased OS and reduced cytokine signaling in DS [49]. Although there is evidence for OS, a conclusion states that AO supplementation is ineffective as a treatment for dementia in DS patients [50].…”