Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation- Induced Hematopoietic Injury.

PURPOSE: Extracellular vesicles (EVs) are shed vesicles that bear a combination of nucleic acids and proteins. EVs are becoming recognized as a mode of cell-to-cell communication. Since hematopoietic stem cells (HSCs) reside in proximity to endothelial cells (ECs), we investigated whether EC-derived EVs could regulate HSC regeneration following ionizing radiation.

METHODS AND MATERIALS: We generated EVs derived from primary murine marrow ECs. We sought to determine the response of irradiated hematopoietic stem and progenitor cells to syngeneic or allogeneic EVs in culture assays. Starting 24 hours following either sub-lethal or lethal irradiation, mice were treated with EVs or saline or cultured, primary marrow endothelial cells to determine the hematopoietic response in vivo.

RESULTS: We demonstrate that EVs bear nuclear material and express EC-specific markers. Treatment with EVs promoted cell expansion and increased colony forming units compared to irradiated, hematopoietic cell cultures treated with cytokines alone. Following total body irradiation, EV- treated mice displayed preserved marrow cellularity, marrow vessel integrity, and prolonged overall survival compared to controls treated with saline. Treatment of irradiated HSPCs with EVs from different genetic strains showed similar results to treatment of HSPCs from syngeneic EVs. Mechanistically, treatment of irradiated HSPCs with EVs resulted in decreased levels of annexin V+ apoptotic cell death, which is mediated in part by tissue inhibitor of metalloproteinase-1.

CONCLUSIONS: Our findings show that syngeneic or allogeneic EVs could be cell-derived therapy to deliver physiologic doses of nucleic acids and growth factors to hematopoietic cells in order to accelerate hematopoietic regeneration.