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A transcriptomic analysis of serial-cultured, tonsil-derived mesenchymal stem cells reveals decreased integrin alpha 3 protein as a potential biomarker of senescent cells

Title
A transcriptomic analysis of serial-cultured, tonsil-derived mesenchymal stem cells reveals decreased integrin alpha 3 protein as a potential biomarker of senescent cells
Authors
Choi, Da HyeonOh, Se-YoungChoi, Ju KwangLee, Kyeong EunLee, Ju YeonPark, Yoon JeongJo, InhoPark, Yoon Shin
Ewha Authors
조인호오세영
SCOPUS Author ID
조인호scopus
Issue Date
2020
Journal Title
STEM CELL RESEARCH & THERAPY
ISSN
1757-6512JCR Link
Citation
STEM CELL RESEARCH & THERAPY vol. 11, no. 1
Keywords
AKTCulture-agedECM-receptor proteinIntegrin alpha 3SenescenceSerial passagingTonsil-derived mesenchymal stem cellsTranscriptome
Publisher
BMC
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Background: Mesenchymal stem cells (MSCs) have been widely used for stem cell therapy, and serial passage of stem cells is often required to obtain sufficient cell numbers for practical applications in regenerative medicine. A long-term serial cell expansion can potentially induce replicative senescence, which leads to a progressive decline in stem cell function and stemness, losing multipotent characteristics. To improve the therapeutic efficiency of stem cell therapy, it would be important to identify specific biomarkers for senescent cells. Methods: Tonsil-derived mesenchymal stem cells (TMSCs) with 20-25 passages were designated as culture-aged TMSCs, and their mesodermal differentiation potentials as well as markers of senescence and stemness were compared with the control TMSCs passaged up to 8 times at the most (designated as young). A whole-genome analysis was used to identify novel regulatory factors that distinguish between the culture-aged and control TMSCs. The identified markers of replicative senescence were validated using Western blot analyses. Results: The culture-aged TMSCs showed longer doubling time compared to control TMSCs and had higher expression of senescence-associated (SA)-beta-gal staining but lower expression of the stemness protein markers, including Nanog, Oct4, and Sox2 with decreased adipogenic, osteogenic, and chondrogenic differentiation potentials. Microarray analyses identified a total of 18,614 differentially expressed genes between the culture-aged and control TMSCs. The differentially expressed genes were classified into the Gene Ontology categories of cellular component (CC), functional component (FC), and biological process (BP) using KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis. This analysis revealed that those genes associated with CC and BP showed the most significant difference between the culture-aged and control TMSCs. The genes related to extracellular matrix-receptor interactions were also shown to be significantly different (p < 0.001). We also found that culture-aged TMSCs had decreased expressions of integrin alpha 3 (ITGA3) and phosphorylated AKT protein (p-AKT-Ser(473)) compared to the control TMSCs. Conclusions: Our data suggest that activation of ECM-receptor signaling, specifically involved with integrin family-mediated activation of the intracellular cell survival-signaling molecule AKT, can regulate stem cell senescence in TMSCs. Among these identified factors, ITGA3 was found to be a representative biomarker of the senescent TMSCs. Exclusion of the TMSCs with the senescent TMSC markers in this study could potentially increase the therapeutic efficacy of TMSCs in clinical applications.
DOI
10.1186/s13287-020-01860-y
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의과대학 > 의학과 > Journal papers
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