Grigorash BB, van Essen D, Liang G, Grosse L, Emelyanov A, Kang Z, Korablev A, Kanzler B, Molina C, Lopez E, Demidov ON, Garrido C, Liu F, Saccani S, Bulavin DV. p16^High senescence restricts cellular plasticity during somatic cell reprogramming. Nat Cell Biol. 2023 Sep;25(9):1265-1278. doi: 10.1038/s41556-023-01214-9. Epub 2023 Aug 31. PMID: 37652981. DOI: 10.1038/s41556-023-01214-9

Summary

Recent research has explored a technique known as four-factor-induced reprogramming (4FR), which helps turn regular body cells into highly versatile stem cells, both in lab settings and in live animals. However, the relationship between this process and cell aging (senescence) is not fully understood. In this study, we used both genetic and chemical methods to remove aging cells from the mix and discovered that this greatly enhances the ability of 4FR to transform these cells into a state resembling the earliest stage of embryonic development. These rejuvenated cells were capable of developing into early forms of embryos and could contribute to both embryonic and extraembryonic tissues. We found that a certain enzyme, which is influenced by aging, plays a crucial role in managing important molecules needed for this transformation. Interestingly, when we combined this reprogramming technique with the removal of aging cells in older mice, it significantly reversed signs of liver aging. Our findings suggest that aging cells can hinder cellular transformation, but removing them can enhance the ability to revert cells to a more primitive and versatile state, potentially refreshing the tissue.

Scientific Abstract

Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that removal of p16^High cells resulted in the 4FR of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the two-cell embryonic state, readily formed implantation-competent blastoids and, following morula aggregation, contributed to embryonic and extraembryonic lineages. We identified senescence-dependent regulation of nicotinamide N-methyltransferase as a key mechanism controlling the S-adenosyl-L-methionine levels during 4FR that was required for expression of the two-cell genes and acquisition of an extraembryonic potential. Importantly, a partial 4F epigenetic reprogramming in old mice was able to reverse several markers of liver aging only in conjunction with the depletion of p16^High cells. Our results show that the presence of p16^High senescent cells limits cell plasticity, whereas their depletion can promote a totipotent-like state and histopathological tissue rejuvenation during 4F reprogramming.