Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 6, Issue 6, Pages 1504-1514Publisher
WILEY
DOI: 10.1002/sctm.15-0394
Keywords
Bone marrow mesenchymal stem cells; Radio-sensitivity; DNA damage response; Cell cycle; PARP-1; ATM
Categories
Funding
- Veterans General Hospital-Taipei [920019]
- National Science Council [101-2314-B-010-028-MY3, 102-2321-B-010-011]
- National Yang-Ming University, Ministry of Education
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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 gamma-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.
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