25. A new isogenic trisomy 21 iPSC resource

      Patient-derived isogenic induced pluripotent stem cells (I-iPSCs) provide a model system to enhance our understanding of the cellular/molecular events leading to disease pathogenesis. Studies using I-iPSCs are especially valuable for revealing factors contributing to complex traits, such as Down syndrome (Ds), which cannot be fully recapitulated in animal models, due to a lack of synteny and differences in brain development/complexities. Thus, the primary aim of this project is to generate 6 new I-iPSC lines using cells from people with trisomy 21 mosaicism (mDs). Reprogramming to form the I-iPSCs from blood or skin specimens followed standard procedures (forced expression of “Yamanaka factors” and a non-integrating Sendai virus). Characterizations of the resulting I-iPSCs include determining the: (1) meiotic/mitotic origin of the extra chromosome 21 in the trisomic cells (trio analysis of SNP allele patterns); (2) biparental versus uniparental status of the chromosomes 21 in the diploid cell line (and confirmation of the constitutional [versus in vitro] origin of the diploid line); and (3) neural ectoderm differentiation potential of the resultant I-iPSCs. The males and females providing specimens for the I-iPSCs show a range of phenotypic traits, including heart abnormalities and developmental delay. Each of the extra chromosomes 21 in the trisomic cells resulted from a meiosis I error. Additional proof of principle” findings identified in a larger mDs cohort showed that disomic/trisomic cell comparisons could unmask trisomy 21-associated differences in telomere length (shorter in trisomic cells; p<0.0001); acquired chromosomal instability (age-related increases in trisomic cells; (p<0.0001); and DNA methylation patterns (133 differentially methylated sites). The availability and use of I-iPSCs for the study of Ds should facilitate teasing apart the cellular mechanisms that contribute to Ds pathology. These isogenic disomy/trisomy 21 iPSCs will be banked and distributed by WiCell and made available to researchers worldwide.
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