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

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.

纳米药物在肿瘤治疗中的现状和挑战

纳米药物在受控给药系统,特别是肿瘤靶向方面具有很多的优点,如生物相容性、血液循环稳定性和减少副作用等,使得纳米药物领域在过去几十年取得了巨大的进展。尽管每年都有大量的相关论文发表,但用于临床治疗的纳米药物却很少。本文旨在探讨纳米药物给药和肿瘤靶向的障碍。纳米药物的合理设计不仅要考虑肿瘤的异质性、体内代谢和理化性质,而且要更有效地创新颗粒制剂以供临床应用。