Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells,Journal of Cellular Physiology

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Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2023-10-06 , DOI: 10.1002/jcp.31132
Jiaming Gao ₁ , Hao Wang ₁ , Junyan Shen ₁ , Xiaojing Liu ₂ , Xiaoqi Zhu ₁ , Ce Huang ₁ , Gongchen Li ₃ , Yao Sun ₃ , Zhongmin Liu _{1,

4} , Yi Eve Sun _{1,

2,

3,

5} , Hailiang Liu _{1,

4}

Affiliation

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 senescence-associated β-galactosidase and P16^ink4a. 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 antiaging 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 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 antiaging roles.

中文翻译：

GDF11和TET2之间的相互调节防止间充质干细胞衰老

生长分化因子 11 (GDF11) 是一种假定的全身性年轻化因子。在这项研究中，我们表征了 GDF11 逆转间充质干细胞 (MSC) 衰老的机制。在培养物中，衰老的 MSC 增殖速度较慢，并且衰老标记物衰老相关 β-半乳糖苷酶和 P16 ^ink4a呈阳性。它们缩短了端粒，降低了 GDF11 表达，并降低了成骨潜力。 GDF11 可以在体外阻断 MSC 衰老，并在体内逆转年龄依赖性骨质流失。 GDF11 的抗衰老作用是通过激活 Smad2/3-PI3K-AKT-mTOR 通路实现的。出乎意料的是，GDF11 还上调了 DNA 去甲基化酶 Tet2，该酶是 GDF11 通过 GDF11 启动子去甲基化自我调节的关键介质。 Tet2 突变通过阻断 GDF11 表达促进 MSC 衰老。 Tet2 调节的 CpG 位点的突变也会阻断 GDF11 的表达，导致 MSC 衰老。 GDF11 和表观遗传因子 Tet2 之间的新型相互调节关系揭示了它们的抗衰老作用。

更新日期：2023-10-06

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