A systems biology approach to Down syndrome: Identification of Notch/Wnt dysregulation in a model of stem cells aging

C.J. Cairney (1) , G. Sanguinetti , E. Ranghini (2) , A.D. Chantry (2) , M.C. Nostro (3) , A. Bhattacharyya (4) , C.N. Svendsen (4) , W.N. Keith (1) , I. Bellantuono (2)

1 Division of Cardiovascular and Medical Sciences
2 University of Sheffield [Sheffield]
3 University Health Network [Toronto, ON, Canada]
4 University of Wisconsin-Madison

Stem cells are central to the development and maintenance of many tissues. This is due to their capacity for extensive proliferation and differentiation into effector cells. More recently it has been shown that the proliferative and differentiative ability of stem cells decrease with age, suggesting that this may play a role in tissue aging. Down Syndrome (DS), is associated with many of the signs of premature tissue aging including T-cell deficiency, increased incidence of early Alzheimer-type and Myelodysplastic-type disease and leukemia. Previously we have shown that both hematopoietic (HSC) and neural stem cells (NSC) in patients affected by DS showed signs of accelerated aging. In this study we tested the hypothesis that changes in gene expression in HSC and NSC of patients affected by DS reflects changes occurring in stem cells with age. The profiles of genes expressed in HSC and NSC from DS patients highlights pathways associated with cellular aging including a downregulation of DNA repair genes and increases in proapoptotic genes, s-phase cell cycle genes, inflammation and angiogenesis genes. Interestingly, Notch signaling was identified as a potential hub, which when deregulated may drive stem cell aging. These data suggests that DS is a valuable model to study early events in stem cell aging.

Mots clés: Trisomy 21; hematopoietic; neural; progenitors; senescence; gene expression; Notch signaling; aging; stem cells

C.J. Cairney, G. Sanguinetti, E. Ranghini, A.D. Chantry, M.C. Nostro, et al.. A systems biology approach to Down syndrome: Identification of Notch/Wnt dysregulation in a model of stem cells aging. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2009, 1792 (4), pp.353. ⟨10.1016/j.bbadis.2009.01.015⟩. ⟨hal-00562896⟩