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Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells.

ABSTRACT: Senescence in human mesenchymal stem cells (MSCs) not only contributes to organism aging and the development of a variety of diseases but also severely impairs their therapeutic properties as a promising cell therapy. Studies searching for efficient biomarkers that represent cellular senescence have attracted much attention; however, no single marker currently provides an accurate cell-free representation of cellular senescence. Here, we studied characteristics of MSC-derived microvesicles (MSC-MVs) that may reflect the senescence in their parental MSCs. We found that senescent late passage (LP) MSCs secreted higher levels of MSC-MVs with smaller size than did early passage (EP) MSCs, and the level of CD105+ MSC-MVs decreased with senescence in the parental MSCs. Also, a substantially weaker ability to promote osteogenesis in MSCs was observed in LP than EP MSC-MVs. Comparative analysis of RNA sequencing showed the same trend of decreasing number of highly-expressed miRNAs with increasing number of passages in both MSCs and MSC-MVs. Most of the highly-expressed genes in LP MSCs and the corresponding MSC-MVs were involved in the regulation of senescence-related diseases, such as Alzheimer's disease. Furthermore, based on the miRNA profiling, transcription factors (TF) and genes regulatory networks of MSC senescence, and the datasets from GEO database, we confirmed that expression of miR-146a-5p in MSC-MVs resembled the senescent state of their parental MSCs. Our findings provide evidence that MSC-MVs are a key factor in the senescence-associated secretory phenotype of MSCs and demonstrate that their integrated characteristics can dynamically reflect the senescence state of MSCs representing a potential biomarker for monitoring MSC senescence.

SUBMITTER: Lei Q

PROVIDER: S-EPMC5558561 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells.

Lei Qian Q Liu Teng T Gao Fei F Xie Hui H Sun Li L Zhao Aiqi A Ren Wenxiang W Guo Hao H Zhang Liming L Wang Hongxiang H Chen Zhichao Z Guo An-Yuan AY Li Qiubai Q

Theranostics 20170706 10

Senescence in human mesenchymal stem cells (MSCs) not only contributes to organism aging and the development of a variety of diseases but also severely impairs their therapeutic properties as a promising cell therapy. Studies searching for efficient biomarkers that represent cellular senescence have attracted much attention; however, no single marker currently provides an accurate cell-free representation of cellular senescence. Here, we studied characteristics of MSC-derived microvesicles (MSC- ...[more]

PMID: 28819455

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Project description:BackgroundThe clinical application of human bone-marrow derived mesenchymal stem cells (MSCs) for the treatment of refractory diseases has achieved remarkable results. However, there is a need for a systematic evaluation of the quality and safety of MSCs sourced from donors. In this study, we sought to assess one potential factor that might impact quality, namely the age of the donor.MethodsWe downloaded two data sets from each of two Gene Expression Omnibus (GEO), GSE39035 and GSE97311 databases, namely samples form young (< 65 years of age) and old (> 65) donor groups. Through, bioinformatics analysis and experimental validation to these retrieved data, we found that MSCs derived from aged donors can lead to differential expression of gene profiles compared with those from young donors, and potentially affect the function of MSCs, and may even induce malignant tumors.ResultsWe identified a total of 337 differentially expressed genes (DEGs), including two upregulated and eight downregulated genes from the databases of both GSE39035 and GSE97311. We further identified 13 hub genes. Six of them, TBX15, IGF1, GATA2, PITX2, SNAI1 and VCAN, were highly expressed in many human malignancies in Human Protein Atlas database. In the MSCs in vitro senescent cell model, qPCR analysis validated that all six hub genes were highly expressed in senescent MSCs. Our findings confirm that aged donors of MSCs have a significant effect on gene expression profiles. The MSCs from old donors have the potential to cause a variety of malignancies. These TBX15, IGF1, GATA2, PITX2, SNAI1, VCAN genes could be used as potential biomarkers to diagnosis aging state of donor MSCs, and evaluate whether MSCs derived from an aged donor could be used for therapy in the clinic. Our findings provide a diagnostic basis for the clinical use of MSCs to treat a variety of diseases.ConclusionsTherefore, our findings not only provide guidance for the safe and standardized use of MSCs in the clinic for the treatment of various diseases, but also provide insights into the use of cell regeneration approaches to reverse aging and support rejuvenation.

Dataset Information

Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells.

Publications

Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells.

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