中科院廣州生物醫(yī)藥與健康研究院裴端卿博士和Miguel Esteban博士研究組成員成功建立了特納氏綜合癥、Warkany綜合癥、13三體綜合癥和Emanuel綜合癥的誘導(dǎo)性多能干細(xì)胞,，并證明了染色體非整倍體不影響重編程的發(fā)生和完成，不影響多能性細(xì)胞的自我更新和分化能力,。
此外,，研究人員對(duì)特納氏綜合癥的IPSCs進(jìn)行了非整倍體對(duì)胚胎早期發(fā)育影響的深入探索，發(fā)現(xiàn)在特納氏綜合癥的誘導(dǎo)性多能干細(xì)胞的早期發(fā)育過(guò)程中,，與胎盤相關(guān)的基因CSF2RA的表達(dá)水平較正常的多能性細(xì)胞低,。
該項(xiàng)研究指出，關(guān)鍵基因表達(dá)劑量的減少可能導(dǎo)致特納綜合癥的胚胎的胎盤發(fā)育不全,，最終引發(fā)流產(chǎn),。該成果近期已發(fā)表在國(guó)際學(xué)術(shù)期刊Human Molecular Genetics。
非整倍體是指整倍染色體中缺少或額外多出一條或若干條染色體,。非整倍體胚胎在早期發(fā)育過(guò)程中約有2/3會(huì)自發(fā)流產(chǎn),，存活到出生后的新生兒一般都有嚴(yán)重的由于器官發(fā)育畸形而導(dǎo)致的生理疾病和智力障礙，嚴(yán)重的在出生后一年內(nèi)死亡,。目前關(guān)于染色體非整倍體綜合癥的發(fā)病機(jī)理不明,，由于材料難以獲得，相關(guān)研究進(jìn)展緩慢,。
該項(xiàng)研究建立的非整倍體誘導(dǎo)性多能干細(xì)胞為進(jìn)一步研究其他非整倍體胚胎早期發(fā)育過(guò)程中出現(xiàn)的問(wèn)題提供了干細(xì)胞來(lái)源,。(生物谷：Bioon.com)
doi:10.1093/hmg/ddr435
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Modeling abnormal early development with induced pluripotent stem cells from aneuploid syndromes
Wen Li1,†, Xianming Wang1,2,†, Wenxia Fan1,†, Ping Zhao1, Yau-Chi Chan3, Shen Chen1, Shiqiang Zhang1, Xiangpeng Guo1, Ya Zhang1, Yanhua Li et al.
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.
