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Hypoxia enhances the radioresistance of mouse mesenchymal stromal cells
- Publication Year :
- 2014
- Publisher :
- Wiley-Blackwell, 2014.
-
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. Stem Cells 2014;32:2188–2200
- Subjects :
- DNA damage
DNA repair
Blotting, Western
mammalian-cells
Fluorescent Antibody Technique
homologous recombination
Biology
medicine.disease_cause
DNA damage response
ionizing-radiation
Radiation Tolerance
hematopoietic stem-cells
bone-marrow-transplantation
Mice
Radioresistance
medicine
Tumor Microenvironment
Animals
RNA, Small Interfering
activation protein-alpha
Tumor microenvironment
irradiation
hypoxia
inducible factor-i
Mesenchymal stem cell
DNA-damage response
histone h2ax phosphorylation
Mesenchymal Stem Cells
Cell Biology
Flow Cytometry
Hypoxia-Inducible Factor 1, alpha Subunit
Cell Hypoxia
Mice, Inbred C57BL
cancer-cells
medicine.anatomical_structure
Gene Knockdown Techniques
Immunology
Cancer cell
Cancer research
Molecular Medicine
Bone marrow
Carcinogenesis
mesenchymal stromal cells
Developmental Biology
DNA Damage
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....b5ad375e36236811742ebdc754b16826