Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks

Wharton’s jelly mesenchymal stem cells (WJ-MSC) exhibit immunomodulatory effects on T cell response. WJ-MSC are easy to collect, process, and proliferate rapidly in culture, but information on the variability of individual cell samples impacting upon in vitro expansion, immunomodulatory potential, and aging processes is still lacking. We propose to evaluate the immunomodulatory cytokine profile and capacity to inhibit T cell proliferation of WJ-MSC progressing to replicative senescence in order to analyze if expected responses are affected. Our results show that the gene expression of immunomodulatory molecules varied among samples with no specific pattern present. In coculture, all WJ-MSC were capable of inhibiting mitogen-activated CD3+ T cell proliferation, although to different degrees, and each PBMC responded with a different level of inhibition. Thus, we suggest that each WJ-MSC displays unique behavior, differing in patterns of cytokine mRNA expression and immunomodulatory capacity. We believe that variability between samples may play a role in the effectiveness of WJ-MSC employed therapeutically.

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Tracking of Replicative Senescence in Mesenchymal Stem Cells by Colony-Forming Unit Frequency

Stem Cells and Aging - Methods in Molecular Biology ◽

10.1007/978-1-62703-317-6_11 ◽

2013 ◽

pp. 143-154 ◽

Cited By ~ 14

Author(s):

Anne Schellenberg ◽

Hatim Hemeda ◽

Wolfgang Wagner

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Replicative Senescence ◽

Colony Forming Unit

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Genome-Wide DNA Methylation Analysis during Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells

Stem Cells International ◽

10.1155/2018/8238496 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Yangyang Cao ◽

Haoqing Yang ◽

Luyuan Jin ◽

Juan Du ◽

Zhipeng Fan

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Osteogenic Differentiation ◽

Biological Process ◽

Cpg Methylation ◽

Genome Wide ◽

Marrow Mesenchymal Stem Cells ◽

Go Terms

Bone marrow mesenchymal stem cells (BMSCs) nowadays are regarded as promising candidates in cell-based therapy for the regeneration of damaged bone tissues that are either incurable or intractable due to the insufficiency of current therapies. Recent studies suggest that BMSCs differentiate into osteoblasts, and that this differentiation is regulated by some specific patterns of epigenetic modifications, such as DNA methylation. However, the potential role of DNA methylation modification in BMSC osteogenic differentiation is unclear. In this study, we performed a genome-wide study of DNA methylation between the noninduced and induced osteogenic differentiation of BMSCs at day 7. We found that the majority of cytosines in a CpG context were methylated in induced BMSCs. Our results also revealed that, along with the induced osteogenic differentiation in BMSCs, the average genomic methylation levels and CpG methylation in transcriptional factor regions (TFs) were increased, the CpG methylation level of various genomic elements was mainly in the medium-high methylation section, and CpG methylation levels in the repeat element had highly methylated levels. The GO analysis of differentially methylated region- (DMR-) associated genes (DMGs) showed that GO terms, including cytoskeletal protein binding (included in Molecular Function GO terms), skeletal development (included in Biological Process GO terms), mesenchymal cell differentiation (included in Biological Process GO terms), and stem cell differentiation (included in Biological Process), were enriched in the hypermethylated DMGs. Then, the KEGG analysis results showed that the WNT pathway, inositol phosphate metabolism pathway, and cocaine addiction pathway were more correlative with the DMRs during the induced osteogenic differentiation in BMSCs. In conclusion, this study revealed the difference of methylated levels during the noninduced and induced osteogenic differentiation of BMSCs and provided useful information for future works to characterize the important function of epigenetic mechanisms on BMSCs’ differentiation.

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Genome‐wide DNA‐methylation profiles in human bone marrow mesenchymal stem cells on titanium surfaces

European Journal Of Oral Sciences ◽

10.1111/eos.12607 ◽

2019 ◽

Vol 127 (3) ◽

pp. 196-209

Author(s):

Mingyue Lyu ◽

Yunfei Zheng ◽

Lingfei Jia ◽

Yan Zheng ◽

Yanping Liu ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Genome Wide ◽

Marrow Mesenchymal Stem Cells ◽

Titanium Surfaces

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Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1471-y ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 15

Author(s):

Jin Seok ◽

Hyun Sook Jung ◽

Sohae Park ◽

Jung Ok Lee ◽

Chong Jai Kim ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Fatty Acid ◽

Mitochondrial Dysfunction ◽

Fatty Acid Oxidation ◽

Replicative Senescence ◽

Acid Oxidation ◽

Differentiation Potential ◽

Passage Number

Abstract Background Human placenta-derived mesenchymal stem cells (PD-MSCs) are powerful sources for cell therapy in regenerative medicine. However, a limited lifespan by senescence through mechanisms that are well unknown is the greatest obstacle. In the present study, we first demonstrated the characterization of replicative senescent PD-MSCs and their possible mitochondrial functional alterations. Methods Human PD-MSCs were cultured to senescent cells for a long period of time. The cells of before passage number 8 were early cells and after passage number 14 were late cells. Also, immortalized cells of PD-MSCs (overexpressed hTERT gene into PD-MSCs) after passage number 14 were positive control of non-senescent cells. The characterization and mitochondria analysis of PD-MSCs were explored with long-term cultivation. Results Long-term cultivation of PD-MSCs exhibited increases of senescent markers such as SA-β-gal and p21 including apoptotic factor, and decreases of proliferation, differentiation potential, and survival factor. Mitochondrial dysfunction was also observed in membrane potential and metabolic flexibility with enlarged mitochondrial mass. Interestingly, we founded that fatty acid oxidation (FAO) is an important metabolism in PD-MSCs, and carnitine palmitoyltransferase1A (CPT1A) overexpressed in senescent PD-MSCs. The inhibition of CPT1A induced a change of energy metabolism and reversed senescence of PD-MSCs. Conclusions These findings suggest that alteration of FAO by increased CPT1A plays an important role in mitochondrial dysfunction and senescence of PD-MSCs during long-term cultivation.

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