Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells
Yi Eve Sun,
Posted 31 Mar 2020
bioRxiv DOI: 10.1101/2020.03.30.008722
Posted 31 Mar 2020
Growth differentiation factor 11 (GDF11) is a putative systemic rejuvenation factor. In this study, we characterized the mechanism by which GDF11 reversed aging of mesenchymal stem cells (MSCs). In culture, aged MSCs proliferate slower, and are positive for senescence markers SA-beta-gal and P16ink4a. They have shortened telomeres, decreased GDF11 expression, and reduced osteogenic potential. GDF11 can block MSC aging in vitro, and reverse age-dependent bone loss in vivo. The anti-aging effect of GDF11 is via activation of the Smad2/3-PI3K-AKT-mTOR pathway. Unexpectedly, GDF11 also upregulated a DNA demethylase Tet2, which served as a key mediator for GDF11 to autoregulate itself via demethylation of specific CpG sites within the GDF11 promoter. Mutation of Tet2 facilitates MSC aging by blocking GDF11 expression. Mutagenesis of Tet2-regulated CpG sites also blocks GDF11 expression, leading to MSC aging. Together, a novel mutual regulatory relationship between GDF11 and an epigenetic factor Tet2 unveiled their anti-aging roles.
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