Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

查看全文 作　　者：Si [1,2,5]Wang;Zheying [1,13]Min;Qianzhao [2,4]Ji;Lingling [5]Geng;Yao [5]Su;Zunpeng [3,4]Liu;Huifang [3,4]Hu;Lixia [2,4]Wang;Weiqi [2,4,5,6,7]Zhang;Keiichiro [9,10]Suzuiki;Yu [11]Huang;Puyao [1]Zhang;Tie-Shan [4,6,12]Tang;Jing [3,4,6]Qu;Yang [1]Yu;Guang-Hui [2,4,5,6,8]Liu;Jie [1,13]Qiao

机构地区：[1]Department of Obstetrics and Gynecology,Center for Reproductive Medicine,Peking University Third Hospital,Beijing 100191,China;[2]National Laboratory of Biomacromolecules,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China;[3]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;[4]University of Chinese Academy of Sciences,Beijing 100049,China;[5]Advanced Innovation Center for Human Brain Protection,National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 100053,China;[6]Institute for Stem cell and Regeneration,Chinese Academy of Sciences,Beijing 100101,China;[7]Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China;[8]Beijing Institute for Brain Disorders,Beijing 100069,China;[9]Institute for Advanced Co-Creation Studies,Osaka University,Osaka 560-8531,Japan;[10]Graduate School of Engineering Science,Osaka University,Osaka 560-8531,Japan;[11]Department of Medical Genetics,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China;[12]State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;[13]Peking-Tsinghua Center for Life Sciences,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing 100871,China

出　　处：《Protein & Cell》索引2020年第11卷第1期,共22页

基　　金：supported by the National Key Research and Development Program of China(2018YFC2000100);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100);the National Key Research and Development Program of China(2018YFA0107203,2017YFA0103304,2017YFA0102802,2016YFC1000601,2015CB 964800,2014CB910503,and 2018YFA0108500);the National Natural Science Foundation of China(Grant Nos.81625009,81330008,91749202,91749123,31671429,81671377,81771515,31601109,31601158,81701388,81601233,81822018,81801399,31801010,81801370,81861168034,81571400,and 81771580);the Program of the Beijing Municipal Science and TechnologyCommission(Z151100003915072);the Key Research Program of the Chinese Academy of Sciences(KJZDEWTZ-L05);the Beijing Municipal Commission of Health and Family Planning(PXM2018_026283_000002);the Advanced Innovation Center for Human Brain Protection(117212,3500-1192012). 摘　　要：Cockayne syndrome(CS)is a rare autosomal recessive inherited disorder characterized by a variety of clinical features,including increased sensitivity to sunlight,progressive neurological abnormalities,and the appearance of premature aging.However,the pathogenesis of CS remains unclear due to the limitations of current disease models.Here,we generate integration-free induced pluripotent stem cells(iPSCs)from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs(GC-iPSCs)using the CRISPR/Cas9 system.CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells(MSCs)and neural stem cells(NSCs),both of which display increased susceptibility to DNA damage stress.Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6.We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives(MSCs and NSCs)in the absence or presence of ultraviolet(UV)and replicative stresses,revealing that defects in DNA repair account for CS pathologies.Moreover,we generate autologous GC-MSCs free of pathogenic mutation under a cGMP(Current Good Manufacturing Practice)-compliant condition,which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS.Collectively,our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS. 关键词：Cockayne syndrome CRISPR/Cas9 GENE CORRECTION disease modelling MESENCHYMAL STEM CELL neural STEM CELL

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Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

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