On March 5th, 2019, Jie Na group from Tsinghua University, China, in collaboration with Ivana Barbaric group from University of Sheffield, United Kingdom, published a paper entitled Anti-apoptotic mutations desensitise human pluripotent stem cells to mitotic stress and enable aneuploid cell survival on Stem Cell Reports. This study first revealed that a commonly found anti-apoptotic copy number variance, BCL2L1, in human pluripotent stem cells (hPSCs) is likely to increase the incidence of aneuploidy formation.
Specialised cells derived from hPSCs have been used for cell replacement therapy, their genome stability is essential for their safety. However, hPSCs often acquire chromosomal abnormality during long-term in vitro culture which limited their application in regenerative medicine. In this study, researchers found that mitotic errors occurred frequently in hPSCs. Aneuploidy will appear if cells with mitotic errors survived. Fortunately, undifferentiated hPSCs express high level of pro-apoptotic protein NOXA, which ensures rapid elimination of cells undergone abnormal division by apoptosis. Knocking-out NOXA but not knocking-down TP53 significantly reduced hPSC’s sensitivity towards mitotic stress. HPSCs frequently acquired 20q11.21 amplification during in vitro culture. 20q11.21 region contains the BCL2L1 gene which encodes the anti-apoptosis protein BCL-XL. Their results revealed that BCL-XL amplified hPSCs displayed high aneuploidy percentage than normal cells under mitotic stress. Therefore, the acquisition of anti-apoptotic mutations significantly increased the risk of acquiring aneuploidy. This study suggested that regular detection of anti-apoptotic mutations should be performed during stem cell culture to avoid further chromosomal variations.
Dr. Jie Na from School of Medicine, Tsinghua University, and Dr Ivana Barbaric from University of Sheffield, UK, are the corresponding authors of this work. Ph.D. candidate, Ms. Jing Zhang is the first author. Collaborators include Dr. Peng Jiang from School of Life Sciences, Tsinghua University. This work also received advice from professor David Huang from the Walter and Eliza Hall Institute of Medical Research, Australia. This research was supported by funding from the National Key R&D Program of China, the National Natural Science Foundation of China (NSFC), the Medical Research Council of the United Kingdom, and the funding from Tsinghua-Peking Center for Life Sciences and core facilities of Tsinghua-Peking Center for Life Sciences.
◎论文链接：
https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(19)30015-3
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