Effects of hypoxia on the response of the haematopoietic system to radiation-induced DNA damage
Calvo Asensio, Irene
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Preparative regimens using DNA damaging agents such as total body irradiation (TBI) prior to bone marrow transplantation (BMT) have profound deleterious effects on the hematopoietic system including the stromal cells that support haematopoiesis and thymopoiesis. Stromal cells are crucial for the successful regeneration of the immune system. This may be one of the main causes for the altered BM architecture and impaired HSC engraftment as well as prolonged periods of lymphopenia and T-cell deficiency common following BMT. The DNA damage response (DDR) is a complex signaling network allowing cells to respond to many different genotoxic insults. Hypoxia is known to modulate the DDR and play a role affecting the survival of different cell types. In this Thesis, the DNA damage response of thymic epithelial cells (TEC), haematopoietic stem cells (HSC), mesenchymal stromal cells (MSC) and DN2 pro-T cells, was characterized, as well as the cell-type specific effects of hypoxia on the DDR. I have shown that, while hypoxia specifically decreases the radio-resistance of mTECs by up-regulating the expression of the pro-apoptotic factor Bim, it increases the radio-resistance of HSCs by enhancing the expression of anti-apoptotic factors such as Bcl-2. In addition, in primary mouse TECs, irradiation caused impaired expression of important genes for TEC function. The molecular mechanism of Hif-1α-mediated increased radio-resistance of MSC in hypoxia has been shown to involve interaction with Arnt to constitute the Hif-1 transcription factor. Hif-1 enhances the DDR of mouse MSCs through the regulation of their transcriptional programme in hypoxia probably regulating DDR protein stability. Finally, the DDR of DN2 pro-T cells has been characterized in vitro and in vivo, and hypoxia-induced phenotypical changes have been described and investigated. These findings have important implications for improving the outcomes of BMT and promoting successful reconstitution of the haematopoietic system.