Mitochondrial DNA Hypomethylation Is a Biomarker Associated with Induced Senescence in Human Fetal Heart Mesenchymal Stem Cells

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Abstract
Background. Fetal heart can regenerate to restore its normal anatomy and function in response to injury, but this regenerative capacity is lost within the first week of postnatal life. Although the specific molecular mechanisms remain to be defined, it is presumed that aging of cardiac stem or progenitor cells may contribute to the loss of regenerative potential. Methods. To study this aging-related dysfunction, we cultured mesenchymal stem cells (MSCs) from human fetal heart tissues. Senescence was induced by exposing cells to chronic oxidative stress/low serum. Mitochondrial DNA methylation was examined during the period of senescence. Results. Senescent MSCs exhibited flattened and enlarged morphology and were positive for the senescence-associated beta-galactosidase (SA-β-Gal). By scanning the entire mitochondrial genome, we found that four CpG islands were hypomethylated in close association with senescence in MSCs. The mitochondrial COX1 gene, which encodes the main subunit of the cytochrome c oxidase complex and contains the differentially methylated CpG island 4, was upregulated in MSCs in parallel with the onset of senescence. Knockdown of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3B) also upregulated COX1 expression and induced cellular senescence in MSCs. Conclusions. This study demonstrates that mitochondrial CpG hypomethylation may serve as a critical biomarker associated with cellular senescence induced by chronic oxidative stress.
Funding Information
  • National Natural Science Foundation of China (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • National Natural Science Foundation of China (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • National Basic Research Program of China (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • California Institute of Regenerative Medicine (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • National Natural Science Foundation of China (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • National Natural Science Foundation of China (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • Technique International Collaboration (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • Key Project of Chinese Ministry of Education (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • National Institutes of Health (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • National Natural Science Foundation of China (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)
  • Development Foundation for Youths of Jilin Provincial Science & Technology Department (81272294, 31430021, 2015CB943303, RT2-01942, 81372835, 81670143, 20130413010GH, 311015, 1RO1ES020812, 81302380, 20140520017JH)

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