title: 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-1α was found to contribute to this enhanced DSB repair by regulating (a) the expression of DNA ligase IV and DNA-PKcs 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.
authors.affiliation: Regenerative Medicine Institute, Department of Physiology, School of Medicine, Nursing and Health Sciences, , National University of Ireland Galway, Ireland; Genome Stability Laboratory, Centre for Chromosome Biology, Department of Biochemistry, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Tara
authors.initials: T
authors.lastname: Sugrue
authors.forename: Noel F
authors.initials: NF
authors.lastname: Lowndes
authors.forename: Rhodri
authors.initials: R
authors.lastname: Ceredig
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D004249:DNA Damage / Q000502:physiology / Q000528:radiation effects; D004260:DNA Repair / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000502:physiology* / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology / Q000528:radiation effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering
keywords: DNA damage response; DNA repair; Hypoxia; Irradiation; Mesenchymal stromal cells