Irradiated mesenchymal stromal cells induce genetic instability in human CD34+ cells

Radiation-induced bystander effects (RIBE) in human hematopoietic stem and progenitor cells may initiate myeloid neoplasms (MN). Here, the occurrence of RIBE caused by genotoxic signaling from irradiated human mesenchymal stromal cells (MSC) on human bone marrow CD34+ cells was investigated. For this purpose, healthy MSC were irradiated in order to generate conditioned medium containing potential genotoxic signaling factors. Afterwards, healthy CD34+ cells from the same donors were grown in conditioned medium and RIBE were analyzed. Increased DNA damage and chromosomal instability were detected in CD34+ cells grown in MSC conditioned medium when compared to CD34+ cells grown in control medium. Furthermore, reactive oxygen species and distinct proteome alterations, e.g., heat-shock protein GRP78, that might be secreted into the extracellular medium, were identified as potential RIBE mediators. In summary, our data provide evidence that irradiated MSC induce genetic instability in human CD34+ cells potentially resulting in the initiation of MN. Furthermore, the identification of key bystander signals, such as GRP78, may lay the framework for the development of next-generation anti-leukemic drugs. * Abbreviations : chtb : chromatid breaks CIN : chromosomal instability DSB : DNA double-strand breaks HSPC : human hematopoietic stem and progenitor cells MN : myeloid neoplasms MSC : mesenchymal stromal cells NO : nitric oxide PBS : phosphate-buffered saline RIBE : radiation-induced bystander effects ROS : reactive oxygen species t-MN : therapy-related MN