Implication de la phosphatase Wip1 induite par le stress dans la régulation de la pluripotence et la différenciation des cellules souches

Despite advances in four factor (4F) reprogramming into a pluripotent state, a roadmap for direct conversion of somatic cells into a totipotent-like state defined as the ability to produce all cell types of an organism, including extraembryonic tissues, is not well established. Using genetic and chemical approaches to manipulate senescent cells, here we found that removal of p16High cells resulted in 4F-induced reprogramming of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the 2-cell (2C) embryonic state, readily formed implantation-competent blastocyst-like structures, blastoids, and following morula aggregation, contributed to embryonic and extraembryonic lineages in E12.5 embryos. We identified senescence(definition)-dependent regulation of nicotinamide N-methyltransferase (NNMT) as a key mechanism controlling the S-adenosyl-L-methionine (SAM) levels during 4F-induced reprogramming that was required for expression of the 2C genes and acquisition of an extraembryonic potential. Importantly, a partial 4F reprogramming in old mice only in conjunction with in vivo depletion of p16High cells was able to significant reverse several cellular markers of aging in the liver. Our results show that the presence of p16High senescent cells limit cell plasticity during 4F-reprogramming, while their depletion can promote totipotency and cellular plasticity in vitro and in vivo.