The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting.
Yuhan ChenJiansen LuYanwen XuYaping HuangDazhuang WangPeiling LiangShaofang RenXuesong HuYewen QinWei KeRalf JauchAndrew Paul HutchinsMei WangFu-Chou TangXiao-Yang ZhaoPublished in: Protein & cell (2022)
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.
Keyphrases
- dna methylation
- induced apoptosis
- induced pluripotent stem cells
- cell fate
- stem cells
- cell cycle arrest
- genome wide
- germ cell
- poor prognosis
- endoplasmic reticulum stress
- signaling pathway
- transcription factor
- embryonic stem cells
- copy number
- endothelial cells
- intellectual disability
- high glucose
- dna damage
- binding protein
- diabetic rats
- autism spectrum disorder
- cell therapy