Modeling Pathogenesis Of Down Syndrome Using Human Induced Pluripotent Sem Cells

Recent advent of induced pluripotent stem cells (iPSCs) has provided a new approach to the establishment of human cellular model of many neurogenetic and neurodegenerative disease. However, most of the studies have focused on neuronal abnormalities and often ignored the role of glial cells in disease phenotypes. To recapitulate the cellular and molecular defects of Down syndrome (DS), we reprogrammed dermal fibroblasts from two patients with DS and two normal individual to iPSC lines, and sequentially differentiated these iPSCs into neurons and astrocytes. Relative to astrocytes derived from control iPSCs, the DS-derived astrocytes exhibited significantly higher levels of amyloid precursor protein (APP) and S100beta, as well as reactive oxygen species (ROS). In neuronal cultures, DS-iPSC and Control-iPSC derived neural stem cells provoke a mild cell-autonomous phenotype in neuronal and astrocytic differentiation efficiency, while impaired neurogenesis and increased gliogenesis were observed when DS-derived neural stem cell were cocultured with DS astrocyte conditioned medium. Moreover, neurons grown on the DS astrocyte monolayer exhibited shorter nerites than those on control astrocytes. As impairment in astrocytic function is increasingly being recognized as an important contributor to neuronal dysfunction, the neuronal abnormalities in DS might arise from the complex interactions between interconnected cell types, because altered protein expression due to trisomy21is not restricted to the affected neuronal populations.