Early Passage Mesenchymal Stem Cells Display Decreased Radiosensitivity and Increased DNA Repair Activity. (24th May 2017)

• Record Type: Journal Article
• Authors: Wu, Po-Kuei; Wang, Jir-You; Chen, Cheng-Fong; Chao, Kuang-Yu; Chang, Ming-Chau; Chen, Wei-Ming; Hung, Shih-Chieh
• Is Part Of: Stem cells translational medicine. Volume 6:Number 6(2017)
• Page Start: 1504
• Page End: 1514
• Publication Date: 2017-05-24
• Subjects: Bone marrow mesenchymal stem cells -- Radio-sensitivity -- DNA damage response -- Cell cycle -- PARP-1 -- ATM; Stem cells -- Periodicals; Regenerative medicine -- Periodicals; Periodicals; 616.0277405
• DOI: 10.1002/sctm.15-0394
• Languages: English
• ISSNs: 2157-6564

Abstract

Abstract: Cell therapies using human mesenchymal stem cells (MSCs) have received much attention in the past decade. In pursuit of the therapeutic potential of MSCs, cell expansion is required to generate a great number of cells with desired phenotype and functionality. Long-term expansion in vitro, however, can lead to altered functions. To explore the changes in DNA damage responses (DDR) in MSCs expanded, DDR pathways following irradiation were characterized in early- and late-passage bone marrow MSCs. Seventy-two hours after irradiation, the percentage of sub-G1 cells in early-passage MSCs did not change significantly. Reduced TUNEL staining was observed in early-passage MSCs compared to late-passage MSCs 4 h after irradiation. Comet assay also revealed that early-passage MSCs were more resistant to irradiation or DNA damages induced by genotoxic agents than late-passage MSCs. ATM phosphorylation and γ-H2AX and phospho-p53 increased in early-passage MSCs while decreased in late-passage MSCs. Through inhibition by KU55933, DDR pathway in early-passage MSCs was shown to be ATM-dependent. Higher levels of poly (ADP-ribose) polymerase-1 (PARP-1) and PAR synthesis were observed in early-passage MSCs than in late-passage MSCs. Knockdown of PARP-1 in early-passage MSCs resulted in sensitization to irradiation-induced apoptosis. Overexpression of PARP-1 in late passage MSCs could render irradiation resistance. Lower activity of DDR in late-passage MSCs was associated with rapid proteasomal degradation of PARP-1. In conclusion, early-passage MSCs are more irradiation-resistant and have increased DDR activity involving PARP-1, ATM and their downstream signals.