Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

Zhai, Yingying; Chen, Xi; Yu, Dehai; Li, Tao; Cui, Jiuwei; Wang, Guanjun; Hu, Ji-Fan; Li, Wei

doi:10.1016/j.yexcr.2015.06.003

Cited by 39 publications

(38 citation statements)

References 46 publications

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“…We then used PCR to quantitate senescence-related genes that have been previously reported [38, 39, 50]. We found that the caveolin-1 gene (CAV1) was upregulated in senescent MSCs (Figure 2(c)), although we did not detect a significant change in APO-J and OX1.…”

Section: Resultsmentioning

confidence: 60%

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

Pian

et al. 2017

Stem Cells International

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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.

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Section: Resultsmentioning

confidence: 60%

“…Cellular senescence was quantitated by measuring the activity of SA- β -Gal as previously described [38, 39]. MSCs were collected and fixed using 3% formaldehyde for 3–5 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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

Pian

et al. 2017

Stem Cells International

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“…In particular, valproic acid, a HDAC inhibitor, and 616452, an Alk5 inhibitor, have been reported to improve efficiency significantly by at least several folds[34–36]. The exact mechanisms by which these chemicals improved reprogramming efficiency were not elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…Dynamic culture did not synergize with valproic acid, suggesting that both of them could be acting along related pathways to improve efficiency. For instance, it has been reported that valproic acid prevented senescence in reprogramming cells possibly by downregulating p16 and p21 expression[34]. The functions of p57, p16 and p21 overlap to some degree in that they all inhibit the activity of Cyclin Dependent Kinases 4 and 6[47–49].…”

Section: Discussionmentioning

confidence: 99%

Dynamic culture improves cell reprogramming efficiency

et al. 2016

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Cell reprogramming to pluripotency is an inefficient process and various approaches have been devised to improve the yield of induced pluripotent stem cells. However, the effect of biophysical factors on cell reprogramming is not well understood. Here we showed that, for the first time, dynamic culture with orbital shaking significantly improved the reprogramming efficiency in adherent cells. Manipulating the viscosity of the culture medium suggested that the improved efficiency is mainly attributed to convective mixing rather than hydrodynamic shear stress. Temporal studies demonstrated that the enhancement of reprogramming efficiency required the dynamic culture in the middle but not early phase. In the early phase, fibroblasts had a high proliferation rate, but as the culture became over-confluent in the middle phase, expression of p57 was upregulated to inhibit cell proliferation and consequently, cell reprogramming. Subjecting the over confluent culture to orbital shaking prevented the upregulation of p57, thus improving reprogramming efficiency. Seeding cells at low densities to avoid over-confluency resulted in a lower efficiency, and optimal reprogramming efficiency was attained at a high seeding density with dynamic culture. Our findings provide insight into the underlying mechanisms of how dynamic culture condition regulate cell reprogramming, and will have broad impact on cell engineering for regenerative medicine and disease modeling.

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“…Cell cycle was analyzed by flow cytometric analysis after popidium iodide (PI) staining 16, 17. Infected cells were seeded onto 6-well plates at a concentration of 1×10 6 /well and incubated for 24 hours.…”

Section: Methodsmentioning

confidence: 99%

Knockdown of COPS3 Inhibits Lung Cancer Tumor Growth in Nude Mice by Blocking Cell Cycle Progression

Pang¹,

Xu²,

Cao³

et al. 2017

J. Cancer

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COPS3 encodes the third subunit of the COP9 signalosome and its aberrant expression is associated with many RITE (“Region of Increased Tumor Expression”) genes in lung cancer tissues. To elucidate the specific role of COPS3 in lung cancer, we examined its expression in lung cancer tissues by immunohistochemical staining. We found that COPS3 was overexpressed in most of the lung cancer samples examined, particularly in small cell carcinoma and squamous cell carcinoma. The expression of COPS3 protein was positively correlated with the level of Ki-67 cell proliferation index (p=0.001) and negatively related to the degree of tumor differentiation (p=0.012). In a xenograft tumor model in nude mice, shRNA-knockdown of COPS3 significantly reduced tumor growth. In lung adenocarcinoma A549 cells, shRNA-knockdown of COPS3 induced cell cycle arrest at G0/G1 phase by upregulating the cell cycle regulator protein P21 and downregulating cyclin B1 and CDK4. These data suggest that COPS3 may promote tumor growth by regulating cell-cycle associated proteins.

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Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

Cited by 39 publications

References 46 publications

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

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

Dynamic culture improves cell reprogramming efficiency

Knockdown of COPS3 Inhibits Lung Cancer Tumor Growth in Nude Mice by Blocking Cell Cycle Progression

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