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

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

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

Author: Yuhan CHEN ¹ ; Jiansen LU ² ; Yanwen XU ¹ ; Yaping HUANG ¹ ; Dazhuang WANG ¹ ; Peiling LIANG ¹ ; Shaofang REN ¹ ; Xuesong HU ¹ ; Yewen QIN ¹ ; Wei KE ³ ; Ralf JAUCH ⁴ ; Andrew Paul HUTCHINS ⁵ ; Mei WANG ¹ ; Fuchou TANG ² ; Xiao-Yang ZHAO ¹
Author Information

1. State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
2. Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China.
3. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
4. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
5. Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: imprinting; reprogramming; spermatogonial stem cell; tetraploid complementation
MeSH: Male; Mice; Animals; Cellular Reprogramming/genetics*; Tetraploidy; Pluripotent Stem Cells/metabolism*; Induced Pluripotent Stem Cells/metabolism*; DNA Methylation; Spermatogonia/metabolism*; Germ Cells/metabolism*
From: Protein & Cell 2023;14(7):477-496
CountryChina
Language:English
Abstract: 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.