摘要
诱导多能干细胞(iPSC)因其强大的自我更新和分化能力而具有广阔的应用前景.然而,多个研究表明体细胞诱导重编程过程会引入数以千计的遗传畸变,进而带来临床应用的安全性问题,已有前期研究证明单核苷酸变异(SNVs)的逐渐积累会致使iPSC丧失发育潜能,但致使SNVs产生并积累的原因还尚未探明.本研究通过对不同DNA损伤修复通路的筛选验证后,发现重编程过程早中期碱基切除修复(BER)效率的不足是导致SNVs积累的重要原因,进一步的研究发现XRCC1可以显著增强重编程前中期的BER,从而降低引入的SNVs,提高iPSC基因组的稳定性.同时,XRCC1介导的BER增强也提高了体细胞诱导重编程的效率.更为重要的是,体内嵌合体实验证实高效的BER可以显著提高iPSC的质量.综上,该研究可以有效提高iPSC基因组的稳定性和多能性,为其临床应用的安全性提供了新思路.
作者
赵堃
孙小翔
郑彩宏
王梦婷
许柱
王明珠
陈嘉瑜
郭明岳
乐融融
吴丽
王祎斌
寇晓晨
赵艳红
殷吉庆
王红
毛志勇
高绍荣
高帅
Kun Zhao;Xiaoxiang Sun;Caihong Zheng;Mengting Wang;Zhu Xu;Mingzhu Wang;Jiayu Chen;Mingyue Guo;Rongrong Le;Li Wu;Yibin Wang;Xiaochen Kou;Yanhong Zhao;Jiqing Yin;Hong Wang;Zhiyong Mao;Shaorong Gao;Shuai Gao(Translational Medical Center for Stem Cell Therapy&Institute for Regenerative Medicine,Shanghai East Hospital,Shanghai Key Laboratory of Signaling and Disease Research,Frontier Science Center for Stem Cell Research,School of Life Sciences and Technology,Tongji University,Shanghai 200120,China;Key Laboratory of Animal Genetics,Breeding and Reproduction of the MARA,National Engineering Laboratory for Animal Breeding,College of Animal Science and Technology,China Agricultural University,Beijing 100193,China;Clinical and Translational Research Center of Shanghai First Maternity&Infant Hospital,Shanghai Key Laboratory of Signaling and Disease Research,Frontier Science Center for Stem Cell Research,School of Life Sciences and Technology,Tongji University,Shanghai 200092,China;Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences,and China National Center for Bioinformation,Beijing 100101,China)
基金
supported by the Natural Key R&D Project of China(2020YFA0113200,2018YFC1003102,and 2021YFC2700300)
the National Natural Science Foundation of China(31721003,31970814,31871438,31820103009,and 82071565)
the 2115 Talent Development Program of China Agricultural University
the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020104)。
