Modeling Abnormal Early Development With Induced Pluripotent Stem Cells From Aneuploid Syndromes

Many human diseases share a developmental origin that only manifests during childhood or maturity. Aneuploid syndromes are caused by supernumerary or reduced number of chromosomes and represent the most extreme example of developmental disease, as they have devastating consequences before or immediately after birth. Investigating how alterations in gene dosage drive these conditions is relevant because it might help treat clinical aspects including mental disability. It may also provide explanations as to how quantitative differences in gene expression determine phenotypic diversity and disease susceptibility among natural populations. Our goal was to produce a panel of induced pluripotent stem cell (iPSC) lines that can be used to improve our understanding of aneuploid syndromes. We have generated iPSCs from 3 donors with monosomy X (Turner Syndrome), 1 with trisomy 8 (Warkany Syndrome 2), 1 with trisomy 13 (Patau Syndrome) and 1 with partial trisomy 11;22 (Derivative 22 Syndrome or Emanuel Syndrome), using skin fibroblasts from affected individuals or amniocytes from antenatal diagnostic tests. The resulting cell lines stably maintain the original karyotype of the donors and behave like embryonic stem cells (ESCs) in all tested assays. Turner Syndrome iPSCs were used for further study including global gene expression analysis and directed differentiation. Multiple clones could be transformed into neural-like, hepatocyte-like and functional heart-like cells, but displayed inadequate up-regulation of placental genes during embryoid body formation. These data support the idea that abnormal organogenesis and early lethality in Turner Syndrome is not caused by a tissue-specific differentiation blockade but rather involves impaired placentation.