The response of mouse mesenchymal stromal cells to radiation-induced DNA double-strand breaks
Sugrue, Tara Kimberly
MetadataShow full item record
This item's downloads: 521 (view details)
Mesenchymal stromal cells (MSCs) are radio-resistant stem cell progenitors that support haematopoiesis in the bone marrow and contribute to the tumour microenvironment. The mechanisms that drive MSC radio-resistance are poorly understood. Ionising radiation (IR) negatively impacts on cell survival largely due to the generation of DNA lesions, particularly of highly genotoxic DNA double-strand breaks (DSBs). The DNA Damage Response (DDR) represents a network of signalling pathways that enable cells to activate biological responses to genotoxic stress, including DNA DSBs. In this study, the role of the DDR in mediating mouse MSC radio-resistance was investigated. Multiple DDR mechanisms synergistically contributed to MSC radio-resistance: robust DDR initiation; DNA damage checkpoint activation and efficient DNA DSB repair. Irradiated mouse MSCs could withstand IR-induced apoptosis; continued to proliferate and could differentiate along mesenchymal-derived lineages. MSCs reside in hypoxic niches within the bone marrow and tumour microenvironments. Herein, hypoxic MSCs exhibited (i) enhanced survival post irradiation; (ii) improved recovery from IR-induced cell cycle arrest and (iii) an increased DNA DSB repair capacity. In addition, HIF-1[alpha] was identified as an important mediator of the increased DNA DSB repair capacity of hypoxic MSCs. Double negative II (DN2) thymocytes are radio-resistant T lymphocyte precursors that reside in the thymus. The mechanisms underlying DN2 radio-resistance are also un-described. Given the important role of the DDR in mediating MSC radio-resistance, the DDR of DN2 thymocytes to IR-induced DNA DSBs was also characterised in this study. Multiple DDR mechanisms were also found to contribute to DN2 radio-resistance including (i) rapid DDR initiation; (ii) induction of a radio-protective G1 checkpoint and (iii) activation of DNA DSB repair. For the first time, this study demonstrates that (i) the DDR is fundamental for mediating mouse MSC resistance to IR-induced DNA DSBs; (ii) hypoxia alters the DDR of irradiated mouse MSCs and (iii) DN2 thymocytes activate the DDR to IR-induced DNA DSBs.
This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. Please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.
The following license files are associated with this item: