Integration-Free Induced Pluripotent Stem Cells Model Genetic andNeural Developmental Features of Down Syndrome Etiology

Down syndrome (DS) is the most frequent cause of humancongenital mental retardation. Cognitive deficits in DSresult from perturbations of normal cellular processesboth during development and in adult tissues, but themechanisms underlying DS etiology remain poorly under-stood. To assess the ability of induced pluripotent stemcells (iPSCs) to model DS phenotypes, as a prototypicalcomplex human disease, we generated bona fide DS andwild-type (WT) nonviral iPSCs by episomal reprogram-ming. DS iPSCs selectively overexpressed chromosome 21genes, consistent with gene dosage, which was associatedwith deregulation of thousands of genes throughout thegenome. DS and WT iPSCs were neurally converted at>95% efficiency and had remarkably similar lineage po-tency, differentiation kinetics, proliferation, and axonextension at early time points. However, at later timepoints DS cultures showed a twofold bias toward glial line-ages. Moreover, DS neural cultures were up to two timesmore sensitive to oxidative stress-induced apoptosis, andthis could be prevented by the antioxidant N-acetylcysteine.Our results reveal a striking complexity in the genetic alter-ations caused by trisomy 21 that are likely to underlie DSdevelopmental phenotypes, and indicate a central role fordefective early glial development in establishing develop-mental defects in DS brains. Furthermore, oxidative stresssensitivity is likely to contribute to the accelerated neurode-generation seen in DS, and we provide proof of concept forscreening corrective therapeutics using DS iPSCs and theirderivatives. Nonviral DS iPSCs can therefore model fea-tures of complex human disease in vitro and provide arenewable and ethically unencumbered discovery platform.