The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting  

作　　者：Yuhan Chen Jiansen Lu Yanwen Xu Yaping Huang Dazhuang Wang Peiling Liang Shaofang Ren Xuesong Hu Yewen Qin Wei Ke Ralf Jauch Andrew Paul Hutchins Mei Wang Fuchou Tang Xiao-Yang Zhao 

机构地区：[1]State Key Laboratory of Organ Failure Research,Department of Developmental Biology,School of Basic Medical Sciences,Southem Medical University,Guangzhou 510515,China [2]Beijing Advanced Innovation Center for Genomics,School of Life Sciences,Peking University,Beijing 100871,China [3]Biomedical Pioneering Innovation Center,Ministry of Education Key Laboratory of Cell Proliferation and Differentiation,Beijing 100871,China [4]Departmentof Urology,Nanfang Hospital,Southem Medical University,Guangzhou 510515,China [5]School of Biomedical Sciences,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong SAR,China [6]Department of Biology,Southerm University of Science and Technology,Shenzhen 518055,China [7]Department of Neonatology,Zhujiang Hospital,Southem Medical University,Guangzhou 510280,China [8]Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering,Southem Medical University,Guangzhou 510515,China [9]Department of Gynecology,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China [10]Key Laboratory of Mental Health of the Ministry of Education,Guangzhou 510515,China [11]Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory),Guangzhou 510005,China [12]Department of Plastic Surgery,Affliated Hangzhou First People's Hospital,Zhejiang University School of Medicine,Hangzhou 310006,China

出　　处：《Protein & Cell》2023年第7期479-498,共20页蛋白质与细胞（英文版）

基　　金：supported by grants from the National Key R&D Program of China(2020YFA0113300 to M.W.,2018YFA0107601 to F.T.,2019YFA0801802 to M.W.,2022YFA0806300 to X.-Y.Z.);the National Natural Science Foundation of China(82071711 to X.-Y.Z.,32170866 to M.W.,U22A20278 to X.-Y.Z.);Key Research&Development Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)(2018GZR110104002 to X.-Y.Z.);Guangdong Basic and Applied Basic Research Foundation(2021A1515010802 to M.W.);National Demonstration Center for Experimental Education of Basic Medical Sciences(Southerm Medical University).

摘　　要：Although somatic cells can be reprogrammed to pluripotent stem cells(PsCs)with pure chemicals,authentic pluripotency of chemically induced pluripotent stem celis(CipsCs)has never been achieved through tetraploid complementation assay.Spontaneous reprogramming of spermatogonial stem cells(ssCs)was another non-transgenic way to obtain PsCs,but this process lacks mechanistic explanation.Here,we reconstructed the trajectory of mouse SsC reprogramming and developed a five-chemical combination,boosting the reprogramming effciency by nearly 80-to 100-folds.More importantly,chemical induced germline-derived PsCs(5C-gPSCs),but not gpsCs and chemical induced pluripotent stem cells,had authentic pluripotency,as determined by tetraploid complementation.Mechanistically,ssCs traversed through an inverted pathway of in vivo germ ceil development,exhibiting the expression signatures and DNA methylation dynamics from spermatogonia to primordial germ cells and further to epiblasts.Besides,ssC-specific imprinting control regions switched from biallelic methylated states to monoallelic methylated states by imprinting demethylation and then re-methylation on one of the two alleles in 5c-gPsCs,which was apparently distinct with the imprinting reprogramming in vivo as DNA methylation simultaneously occurred on both alleles.Our work sheds ight on the unique regulatory network underpinning SsC reprogramming,providing insights to understand generic mechanisms for cell-fate decision and epigenetic-relateddisorders in regenerative medicine.

关 键 词：REPROGRAMMING spermatogonial stem cell tetraploid complementation IMPRINTING 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]