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p16High senescence restricts cellular plasticity during somatic cell reprogramming
Bogdan B Grigorash1,2, Dominic van Essen1, Guixian Liang3,4
1Institute for Research on Cancer and Aging of Nice (IRCAN), Université Côte d'Azur, INSERM, CNRS, Nice, France.
Nature Cell Biology
|August 31, 2023
Summary
Removing senescent cells enhances four-factor reprogramming (4FR) of somatic cells into totipotent-like stem cells. This process rejuvenates aged tissues by promoting cell plasticity and reversing aging markers.
Area of Science:
- Cellular reprogramming
- Aging biology
- Stem cell research
Background:
- Four-factor reprogramming (4FR) advances in vitro and in vivo, but its interplay with cellular senescence is understudied.
- Senescence, a state of irreversible cell cycle arrest, is linked to aging and tissue dysfunction.
Purpose of the Study:
- To investigate the role of senescent cells in 4FR.
- To explore the potential of manipulating senescence for regenerative purposes.
Main Methods:
- Genetic and chemical depletion of p16High senescent cells.
- Four-factor reprogramming of somatic cells.
- Analysis of pluripotency markers, two-cell embryonic state markers, blastoid formation, and embryonic/extraembryonic lineage contribution.
- Investigation of nicotinamide N-methyltransferase regulation and S-adenosyl-L-methionine levels.
- Partial 4F epigenetic reprogramming in aged mice with and without senescent cell depletion.
Main Results:
- Depletion of p16High senescent cells enabled 4FR into totipotent-like stem cells expressing pluripotency and two-cell embryonic markers.
- These reprogrammed cells formed implantation-competent blastoids and contributed to embryonic lineages.
- Senescence-dependent regulation of nicotinamide N-methyltransferase was identified as crucial for 4FR and extraembryonic potential.
- Partial 4FR combined with senescent cell depletion reversed liver aging markers in old mice.
Conclusions:
- p16High senescent cells restrict cell plasticity during 4FR.
- Senescent cell depletion promotes a totipotent-like state and tissue rejuvenation.
- Targeting senescence is a viable strategy to enhance reprogramming and combat aging.
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