title: Modeling abnormal early development with induced pluripotent stem cells from aneuploid syndromes.
abstract: Many human diseases share a developmental origin that manifests during childhood or maturity. Aneuploid syndromes are caused by supernumerary or reduced number of chromosomes and represent an extreme example of developmental disease, as they have devastating consequences before and after birth. Investigating how alterations in gene dosage drive these conditions is relevant because it might help treat some clinical aspects. It may also provide explanations as to how quantitative differences in gene expression determine phenotypic diversity and disease susceptibility among natural populations. Here, we aimed to produce induced pluripotent stem cell (iPSC) lines that can be used to improve our understanding of aneuploid syndromes. We have generated iPSCs from monosomy X [Turner syndrome (TS)], trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome) and partial trisomy 11;22 (Emanuel syndrome), using either skin fibroblasts from affected individuals or amniocytes from antenatal diagnostic tests. These cell lines stably maintain the karyotype of the donors and behave like embryonic stem cells in all tested assays. TS iPSCs were used for further studies including global gene expression analysis and tissue-specific directed differentiation. Multiple clones displayed lower levels of the pseudoautosomal genes ASMTL and PPP2R3B than the controls. Moreover, they could be transformed into neural-like, hepatocyte-like and heart-like cells, but displayed insufficient up-regulation of the pseudoautosomal placental gene CSF2RA during embryoid body formation. These data support that abnormal organogenesis and early lethality in TS are not caused by a tissue-specific differentiation blockade, but rather involves other abnormalities including impaired placentation.
authors.affiliation: Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Xianming
authors.initials: X
authors.lastname: Wang
authors.forename: Wenxia
authors.initials: W
authors.lastname: Fan
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Yau-Chi
authors.initials: YC
authors.lastname: Chan
authors.forename: Shen
authors.initials: S
authors.lastname: Chen
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Zhang
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Guo
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Li
authors.forename: Jinglei
authors.initials: J
authors.lastname: Cai
authors.forename: Dajiang
authors.initials: D
authors.lastname: Qin
authors.forename: Xingyan
authors.initials: X
authors.lastname: Li
authors.forename: Jiayin
authors.initials: J
authors.lastname: Yang
authors.forename: Tianran
authors.initials: T
authors.lastname: Peng
authors.forename: Daniela
authors.initials: D
authors.lastname: Zychlinski
authors.forename: Dirk
authors.initials: D
authors.lastname: Hoffmann
authors.forename: Ruosi
authors.initials: R
authors.lastname: Zhang
authors.forename: Kang
authors.initials: K
authors.lastname: Deng
authors.forename: Kwong-Man
authors.initials: KM
authors.lastname: Ng
authors.forename: Bjorn
authors.initials: B
authors.lastname: Menten
authors.forename: Mei
authors.initials: M
authors.lastname: Zhong
authors.forename: Jiayan
authors.initials: J
authors.lastname: Wu
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Chen
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
mesh_terms: D000782:Aneuploidy; D002454:Cell Differentiation; D002478:Cells, Cultured; D025063:Chromosome Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D007223:Infant; D008297:Male; D008957:Models, Genetic