In Vitro Cellular & Developmental Biology - Animal ( IF 1.5 ) Pub Date : 2024-01-02 , DOI: 10.1007/s11626-023-00824-9 Kana Yanagihara 1 , Yohei Hayashi 2 , Yujung Liu 1 , Tomoko Yamaguchi 3 , Yasuko Hemmi 2 , Minako Kokunugi 1, 4 , Kozue Uchio Yamada 5 , Ken Fukumoto 1, 6 , Mika Suga 1 , Satoshi Terada 6 , Hiroki Nikawa 4 , Kenji Kawabata 3 , Miho Furue 1, 7
Trisomy 12 is one of the most frequent chromosomal abnormalities in cultured human pluripotent stem cells (hPSCs). Although potential oncogenic properties and augmented cell cycle caused by trisomy 12 have been reported, the consequences of trisomy 12 in terms of cell differentiation, which is the basis for regenerative medicine, drug development, and developmental biology studies, have not yet been investigated. Here, we report that trisomy 12 compromises the mesendodermal differentiation of hPSCs. We identified sublines of hPSCs carrying trisomy 12 after their prolonged culture. Transcriptome analysis revealed that these hPSC sublines carried abnormal gene expression patterns in specific signaling pathways in addition to cancer-related cell cycle pathways. These hPSC sublines showed a lower propensity for mesendodermal differentiation in embryoid bodies cultured in a serum-free medium. BMP4-induced exit from the self-renewal state was impaired in the trisomy 12 hPSC sublines, with less upregulation of key transcription factor gene expression. As a consequence, the differentiation efficiency of hematopoietic and hepatic lineages was also impaired in the trisomy 12 hPSC sublines. We reveal that trisomy 12 disrupts the genome-wide expression patterns that are required for proper mesendodermal differentiation.
中文翻译:
12 三体损害人类多能干细胞的中内胚层分化倾向
12 三体是培养的人类多能干细胞 (hPSC) 中最常见的染色体异常之一。尽管已报道了 12 三体性引起的潜在致癌特性和增强的细胞周期,但 12 三体性在细胞分化方面的后果尚未得到研究,而细胞分化是再生医学、药物开发和发育生物学研究的基础。在此,我们报告 12 三体性损害 hPSC 的中内胚层分化。我们在长期培养后鉴定出携带 12 三体性的 hPSC 亚系。转录组分析显示,除了癌症相关的细胞周期途径外,这些 hPSC 亚系在特定信号传导途径中还携带异常基因表达模式。这些 hPSC 亚系在无血清培养基中培养的胚状体中表现出较低的中内胚层分化倾向。在 12 三体 hPSC 亚系中,BMP4 诱导的自我更新状态退出受到损害,关键转录因子基因表达的上调较少。因此,12 三体 hPSC 亚系的造血和肝谱系的分化效率也受到损害。我们发现 12 三体破坏了中内胚层正确分化所需的全基因组表达模式。