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Stem Cells International
Volume 2017 (2017), Article ID 1764549, 12 pages
Research Article

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

1Stem Cell and Cancer Center, The First Bethune Hospital, Jilin University, Changchun, Jilin 130061, China
2Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA
3Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA

Correspondence should be addressed to Pinchas Cohen, Jiuwei Cui, Andrew R. Hoffman, and Ji-Fan Hu

Received 18 October 2016; Revised 5 January 2017; Accepted 16 January 2017; Published 6 April 2017

Academic Editor: Martin Stimpfel

Copyright © 2017 Dehai Yu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.