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Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells

Jiaming Gao1, Hao Wang1, Junyan Shen1

  • 1Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Journal of Cellular Physiology
|October 6, 2023
PubMed

Insights

Growth Differentiation Factor 11 (GDF11) rejuvenates aging mesenchymal stem cells (MSCs) by activating key pathways and upregulating the DNA demethylase Tet2. This establishes a novel feedback loop crucial for maintaining cellular youth and function.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Epigenetics

Background:

  • Aging mesenchymal stem cells (MSCs) exhibit reduced proliferation, senescence markers, and impaired osteogenic potential.
  • Growth Differentiation Factor 11 (GDF11) is implicated as a systemic factor with potential anti-aging properties.
  • Understanding the molecular mechanisms of GDF11 in MSC aging is critical for regenerative medicine.

Purpose of the Study:

  • To elucidate the mechanism by which GDF11 reverses aging in mesenchymal stem cells (MSCs).
  • To investigate the role of GDF11 in regulating cellular senescence and stem cell function.
  • To identify novel molecular pathways involved in GDF11-mediated anti-aging effects.

Main Methods:

  • Characterization of aged MSCs regarding proliferation, senescence markers (β-galactosidase, P16ink4a), telomere length, GDF11 expression, and osteogenic potential.
  • In vitro and in vivo experiments assessing the effects of GDF11 on MSC aging and bone loss.
  • Analysis of the Smad2/3-PI3K-AKT-mTOR pathway activation by GDF11.
  • Investigation of GDF11's interaction with the DNA demethylase Tet2 and its impact on GDF11 promoter methylation.

Main Results:

  • GDF11 treatment blocked MSC aging in vitro and reversed age-dependent bone loss in vivo.
  • GDF11's anti-aging effects were mediated through the activation of the Smad2/3-PI3K-AKT-mTOR pathway.
  • GDF11 upregulated Tet2, a DNA demethylase that autoregulates GDF11 expression via promoter demethylation.
  • Tet2 deficiency or mutagenesis of Tet2-regulated CpG sites impaired GDF11 expression and accelerated MSC aging.

Conclusions:

  • GDF11 effectively reverses MSC aging and improves stem cell function through specific molecular pathways.
  • A novel mutual regulatory relationship exists between GDF11 and the epigenetic factor Tet2, highlighting their combined anti-aging roles.
  • This study uncovers a critical epigenetic mechanism involving Tet2 in GDF11-mediated rejuvenation, offering potential therapeutic targets for age-related decline.
Keywords:
TET2cell senescencemesenchymal stem cells

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