Hypoxia Enhances the Radioresistance of Mouse Mesenchymal Stromal Cells

Abstract

Mesenchymal stromal cells (MSCs) are radioresistant bone marrow progenitors that support hematopoiesis and its reconstitution following total body irradiation. MSCs reside in hypoxic niches within the bone marrow and tumor microenvironments. The DNA damage response (DDR) represents a network of signaling pathways that enable cells to activate biological responses to DNA damaging agents. Hypoxia-mediated alterations in the DDR contribute to the increased radioresistance of hypoxic cancer cells, limiting therapeutic efficacy. The DDR is important in mediating mouse MSC radioresistance. However, the effects of hypoxia on MSC radioresistance are currently unknown. In this report, hypoxia was found to (a) increase MSC proliferation rate and colony size; (b) increase long-term survival post-irradiation (IR), and (c) improve MSC recovery from IR-induced cell cycle arrest. DNA double-strand break (DSB) repair in MSCs was upregulated in hypoxia, accelerating the resolution of highly genotoxic IR-induced DNA DSBs. In addition, HIF-1a was found to contribute to this enhanced DSB repair by regulating (a) the expression of DNA ligase IV and DNA-PK cs and (b) Rad51 foci formation in response to DNA DSBs in hypoxic MSCs. We have demonstrated, for the first time, that hypoxia enhances mouse MSC radioresistance in vitro. These findings have important implications for our understanding of MSC functions in supporting allogeneic bone marrow transplantation and in tumorigenesis.

Should hypoxia preconditioning become the standardized procedure for bone marrow MSCs preparation for clinical use?

“…In vitro cell expansion under hypoxic conditions has been shown to favor proliferation, viability, colony-forming efficiency and migration ability, although maintaining immunophenotype and cell cycle and enhancing the radioresistance potential [3][4][5][6][7][8]. Importantly, hypoxia preconditioning for 48 hours was demonstrated to enhance the survival and retention of MSCs in immune deficient mice after intramuscular injection [9].…”

Differential Response of Mouse Thymic Epithelial Cell Types to Ionizing Radiation-Induced DNA Damage

“…Our group has previously identified hypoxia as an enhancer of the DDR of mesenchymal stromal cells (27). For this reason, we also studied the effects of hypoxia on the radio-resistance of our TEC cell lines.…”

“…Here, we characterized the DDR of TEC lines in order to identify the main mechanisms underlying their survival after IR and compared the specific responses of cortical and medullary TECs. Since we previously demonstrated a role of hypoxia in enhancing the DDR of mesenchymal stromal cells (27), we also analyzed whether hypoxia plays a role in regulating TEC response to IR. We show how exposure to IR has a profound effect on primary mouse TEC functionality by markedly decreasing their expression of factors that are essential for their functions.…”

Effect of Radiotherapy Dose Rates on Early Intestinal Toxicity

“…It is known that hypoxia enhances the radioresistance of non-maling cells such as mesenchymal stromal cells. [26] In applications of intensity-modulated radiotherapy (IMRT), decrease in response to treatment may occur due to overall prolongation of treatment time. However, it has been thought that this condition is compensated by rapid oxygenation.…”