Weissbein Uri, Peretz Mordecai, Plotnik Omer, Yanuka Ofra, Sagi Ido, Golan-Lev Tamar, Benvenisty Nissim
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
iScience. 2019 Jan 25;11:398-408. doi: 10.1016/j.isci.2018.12.031. Epub 2019 Jan 3.
Human pluripotent stem cells (hPSCs) acquire genetic changes during their propagation in culture that can affect their use in research and future therapies. To identify the key genes involved in selective advantage during culture adaptation and tumorigenicity of hPSCs, we generated a genome-wide screening system for genes and pathways that provide a growth advantage either in vitro or in vivo. We found that hyperactivation of the RAS pathway confers resistance to selection with the hPSC-specific drug PluriSIn-1. We also identified that inactivation of the RHO-ROCK pathway gives growth advantage during culture adaptation. Last, we demonstrated the importance of the PI3K-AKT and HIPPO pathways for the teratoma formation process. Our screen revealed key genes and pathways relevant to the tumorigenicity and survival of hPSCs and should thus assist in understanding and confronting their tumorigenic potential.
人类多能干细胞（hPSCs）在体外培养过程中会发生基因变化，这可能会影响它们在研究和未来治疗中的应用。为了确定在hPSCs的培养适应和致瘤性过程中涉及选择性优势的关键基因，我们构建了一个全基因组筛选系统，用于筛选在体外或体内提供生长优势的基因和信号通路。我们发现，RAS信号通路的过度激活赋予了对hPSC特异性药物PluriSIn-1筛选的抗性。我们还确定，RHO-ROCK信号通路的失活在培养适应过程中提供了生长优势。最后，我们证明了PI3K-AKT和HIPPO信号通路在畸胎瘤形成过程中的重要性。我们的筛选揭示了与hPSCs的致瘤性和存活相关的关键基因和信号通路，因此应有助于理解和应对它们的致瘤潜力。
