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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
PubMed

Insights

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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