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

Chen, Yuhan1; Lu, Jiansen2,3; Xu, Yanwen1,12; Huang, Yaping1; Wang, Dazhuang1; Liang, Peiling1; Ren, Shaofang1; Hu, Xuesong1; Qin, Yewen1; Ke, Wei4; Jauch, Ralf5; Hutchins, Andrew Paul6; Wang, Mei1,7; Tang, Fuchou2,3; Zhao, Xiao-Yang1,8,9,10,11

2022-11-01

10.1093/procel/pwac044

Protein & Cell   Impact Factor & Quartile

1674-800X

1674-8018

Although somatic cells can be reprogrammed to pluripotent stem cells (PSCs) with pure chemicals, authentic pluripotency of chemically induced pluripotent stem cells (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 efficiency 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 cell 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 light on the unique regulatory network underpinning SSC reprogramming, providing insights to understand generic mechanisms for cell-fate decision and epigenetic-related disorders in regenerative medicine.

reprogramming spermatogonial stem cell tetraploid complementation imprinting

SCI

English

Others

National Key R&D Program of China["2020YFA0113300","2018YFA0107601","2019YFA0801802","2022YFA0806300"] ; National Natural Science Foundation of China["82071711","32170866","U22A20278"] ; Key Research & Development Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)[2018GZR110104002] ; Guangdong Basic and Applied Basic Research Foundation[2021A1515010802]

Cell Biology

Cell Biology

WOS:000949878600001

OXFORD UNIV PRESS

Web of Science

1.Southern Med Univ, Sch Basic Med Sci, Dept Dev Biol, State Key Lab Organ Failure Res, Guangzhou 510515, Peoples R China
2.Peking Univ, Beijing Adv Innovat Ctr Genom, Sch Life Sci, Beijing 100871, Peoples R China
3.Minist Educ, Biomed Pioneering Innovat Ctr, Key Lab Cell Proliferat & Differentiat, Beijing 100871, Peoples R China
4.Southern Med Univ, Nanfang Hosp, Dept Urol, Guangzhou 510515, Peoples R China
5.Univ Hong Kong, Li Ka Shing Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China
6.Southern Univ Sci & Technol, Dept Biol, Shenzhen 518055, Peoples R China
7.Southern Med Univ, Zhujiang Hosp, Dept Neonatol, Guangzhou 510280, Peoples R China
8.Southern Med Univ, Guangdong Prov Key Lab Construction & Detect Tissu, Guangzhou 510515, Peoples R China
9.Southern Med Univ, Zhujiang Hosp, Dept Gynecol, Guangzhou 510280, Peoples R China
10.Minist Educ, Key Lab Mental Hlth, Guangzhou 510515, Peoples R China
11.Guangzhou Regenerat Med & Hlth Guangdong Lab, Bioland Lab, Guangzhou 510005, Peoples R China
12.Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Sch Med, Dept Plast Surg, Hangzhou 310006, Peoples R China

Chen, Yuhan,Lu, Jiansen,Xu, Yanwen,et al. The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting[J]. Protein & Cell,2022.

Chen, Yuhan.,Lu, Jiansen.,Xu, Yanwen.,Huang, Yaping.,Wang, Dazhuang.,...&Zhao, Xiao-Yang.(2022).The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting.Protein & Cell.

Chen, Yuhan,et al."The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting".Protein & Cell (2022).