Epigenetic regulation of miR-29a/miR-30c/DNMT3A axis controls SOD2 and mitochondrial oxidative stress in human mesenchymal stem cells

Redox Biology

Myoung-Hee Kang¹  Supyong Hwang²  Seul-Ki Park³  Jai-Hee Moon⁴  Dong-Hoon Jin⁴  Nayoung Suh⁴  Choung Soo Kim⁴  Jae-Sik Shin⁴  Dalsan You⁴  Joo-Yong Lee⁴  Yi-deun Jung⁴  Dayeon Kang⁴  Yun-Yong Park⁵  Seung-Woo Hong⁶  Jung Jin Hwang⁷ 

[1] Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea;Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea;Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea;Asan Institute for Life Sciences, Asan Medical Center, Seoul, 05505, Republic of Korea;Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea;Department of Pharmaceutical Engineering, College of Medical Sciences, Soon Chun Hyang University, Asan, 31538, Republic of Korea;Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea;

关键词: Cellular senescence;    Mitochondrial oxidative stress;    microRNAs;    DNMT3A;    SOD2;    Human mesenchymal stem cells;   

DOI  :  

来源: DOAJ

【 摘 要 】

The use of human mesenchymal stem cells (hMSCs) in clinical applications requires large-scale cell expansion prior to administration. However, the prolonged culture of hMSCs results in cellular senescence, impairing their proliferation and therapeutic potentials. To understand the role of microRNAs (miRNAs) in regulating cellular senescence in hMSCs, we globally depleted miRNAs by silencing the DiGeorge syndrome critical region 8 (DGCR8) gene, an essential component of miRNA biogenesis. DGCR8 knockdown hMSCs exhibited severe proliferation defects and senescence-associated alterations, including increased levels of reactive oxygen species (ROS). Transcriptomic analysis revealed that the antioxidant gene superoxide dismutase 2 (SOD2) was significantly downregulated in DGCR8 knockdown hMSCs. Moreover, we found that DGCR8 silencing in hMSCs resulted in hypermethylation in CpG islands upstream of SOD2. 5-aza-2′-deoxycytidine treatment restored SOD2 expression and ROS levels. We also found that these effects were dependent on the epigenetic regulator DNA methyltransferase 3 alpha (DNMT3A). Using computational and experimental approaches, we demonstrated that DNMT3A expression was regulated by miR-29a-3p and miR-30c-5p. Overexpression of miR-29a-3p and/or miR-30c-5p reduced ROS levels in DGCR8 knockdown hMSCs and rescued proliferation defects, mitochondrial dysfunction, and premature senescence. Our findings provide novel insights into hMSCs senescence regulation by the miR-29a-3p/miR-30c-5p/DNMT3A/SOD2 axis.

【 授权许可】

Unknown