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Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1-related genes and impairs DNA double-strand break recognition.
FEBS Open Bio 10, 1238-1250 (2020)
Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell-based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome-based pathway analysis of in vitro-expanded human bone marrow-derived mesenchymal stem cell (hBM-MSCs), supplemented with cellular assays focusing on DNA double-strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination (HR), cell cycle control, and chromosomal replication. Assays for the recognition (gamma-H2AX + 53BP1 foci) and repair (pBRCA1 + gamma-H2AX foci) of X-ray-induced DNA DSBs in hBM-MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by HR (e.g., Rad51, Rad54, BRCA1) show a 2.3- to fourfold reduction of their mRNA expression by qRT-PCR. We conclude that the in vitro expansion of hMSCs can lead to aging-related impairment of the recognition and repair of DNA breaks.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Brca1 ; Cellular Aging ; Dna Repair ; Homologous Recombination ; Mesenchymal Stem Cells; Stromal Cells; Abc Transporters; Bone-marrow; Therapy; Resistant; Senescence; Expression; Autophagy; Pattern
Language
english
Publication Year
2020
HGF-reported in Year
2020
ISSN (print) / ISBN
2211-5463
Journal
FEBS Open Bio
Quellenangaben
Volume: 10,
Issue: 7,
Pages: 1238-1250
Publisher
Elsevier
Publishing Place
Cambridge
Reviewing status
Peer reviewed
Institute(s)
Institute of Radiation Biology (ISB)
POF-Topic(s)
30202 - Environmental Health
Research field(s)
Radiation Sciences
PSP Element(s)
G-500200-001
WOS ID
WOS:000538851400001
Scopus ID
85086113075
PubMed ID
32333827
Erfassungsdatum
2020-05-07