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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 γ‐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 IR‐induced 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. S TEM  C ells  2013;31:137–145

Multiple Facets of the DNA Damage Response Contribute to the Radioresistance of Mouse Mesenchymal Stromal Cell Lines