The regeneration of the hematopoietic system following total body irradiation is supported by host-derived mesenchymal stromal cells (MSCs) within the bone marrow. The mechanisms used by MSCs to survive radiation doses that are lethal to the hematopoietic system are poorly understood. The DNA damage response (DDR) represents a cohort of signaling pathways that enable cells to execute biological responses to genotoxic stress. Here, we examine the role of the DDR in mediating the resistance of MSCs to ionizing radiation (IR) treatment using two authentic clonal mouse MSC lines, MS5 and ST2, and primary bulk mouse MSCs. We show that multiple DDR mechanisms contribute to the radio-resistance of MSCs: robust DDR activation via rapid c-H2AX formation, activation of effective S and G 2 / M DNA damage checkpoints, and efficient repair of IR-induced DNA double-strand breaks. We show that MSCs are intrinsically programmed to maximize survival following IR treatment by expressing high levels of key DDR proteins including ATM, Chk2, and DNA Ligase IV; high levels of the anti-apoptotic, Bcl-2 and Bcl-XL ; and low levels of the pro-apoptotic, Bim and Puma. As a result, we demonstrate that irradiated mouse MSCs withstand IRinduced genotoxic stress, continue to proliferate, and retain their capacity to differentiate long-term along mesenchymal-derived lineages. We have shown, for the first time, that the DDR plays key roles in mediating the radioresistance of mouse MSCs which may have important implications for the study and application of MSCs in allogeneic bone marrow transplantation, graft-versus-host disease, and cancer treatment. STEM CELLS 2013;31:137-145 Disclosure of potential conflicts of interest is found at the end of this article.
Mesenchymal stromal cells (MSCs) are multi‐potent adult stem cells located in various tissues, including the bone marrow. MSCs are key components of the haematopoietic stem cell (HSC) niche within the bone marrow where they function to maintain haematopoietic homoeostasis by regulating HSC self‐renewal and function. Bone marrow exposure to ionising radiation causes rapid depletion of radio‐sensitive HSCs and their progenitors, leading to haematopoietic failure. However, host‐/patient‐derived MSCs can survive radiation doses lethal to the haematopoietic system. The mechanisms underlying MSC radio‐resistance are currently under intense investigation. Here, we review the current knowledge of MSC radio‐biology. The DNA damage response (DDR) represents an orchestrated network of signalling pathways that enable cells to respond to genotoxic damage. We discuss in detail the emerging importance of the DDR in mediating MSC radio‐resistance and examine the DDR of MSCs in the context of other stem cell types. Finally, we examine future advances in understanding MSC radio‐resistance and discuss the potential impact of the radio‐resistance of these stem cells for the clinic.
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.
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