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Substrate stiffness dictates unique paths towards proliferative arrest in WI-38 cells.

Alyssa M Kaiser1, Amirali Selahi1, Wenjun Kong1

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Area of Science:

  • Cell Biology
  • Mechanobiology
  • Aging Research

Background:

  • Finite replicative potential is a hallmark of somatic cells, leading to replicative senescence via telomere shortening.
  • Telomerase reverse transcriptase (hTERT) can overcome replicative arrest.
  • Mechanotransduction pathways, like YAP signaling, are activated as cells approach senescence, but their role in replicative lifespan is unclear.

Purpose of the Study:

  • To investigate how the mechanical environment, specifically substrate stiffness, influences the replicative lifespan and senescence trajectory of WI-38 human lung fibroblasts.
  • To explore the interplay between mechanosensation and telomere-driven replicative arrest.

Main Methods:

  • WI-38 cells were cultured on substrates of varying stiffness.
  • Proliferation rates, cellular phenotypes, and gene expression were analyzed.
  • Bulk and single-cell RNA-sequencing and ATAC-sequencing were employed.
  • The effects of ectopic hTERT expression were assessed.

Main Results:

  • Matrix softening reduced WI-38 cell proliferation and shortened their proliferative lifespan.
  • Softer substrates induced unique cellular phenotypes and a distinct G1 transcriptional state characterized by an AP-1 program.
  • Ectopic hTERT expression mitigated or abolished the effects of substrate stiffness on proliferation and senescence.
  • The AP-1 transcription factor program on soft substrates was not observed in hTERT-expressing cells.

Conclusions:

  • The mechanical environment significantly alters WI-38 cell proliferative lifespan and influences the pathways leading to growth arrest.
  • Substrate stiffness can dictate unique cellular responses, including specific transcriptional programs, that contribute to senescence.
  • Telomerase activity, through hTERT, can override the impact of mechanical cues on cellular aging and proliferation.