The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting
Received date: 23 May 2022
Accepted date: 13 Sep 2022
Published date: 15 Jul 2023
Copyright
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.
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 . The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting[J]. Protein & Cell, 2023 , 14(7) : 477 -496 . DOI: 10.1093/procel/pwac044
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