Mesenchymal Stem Cell-Derived Extracellular Vesicles Improve Survival and Enhance Hematopoietic Recovery in Mice Exposed to High-Dose Irradiation.

Exposure to high-dose radiation often results in hematopoietic acute radiation syndromes, leading to early mortality, while current therapies for patients exposed to lethal radiation doses are limited. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in tissue repair and regeneration but have not been well investigated for mitigating high-dose radiation damage. We previously demonstrated that human or murine MSC-EVs can reverse bone marrow injury caused by mild or moderate radiation. The current study evaluated the therapeutic potential of human MSC-EVs in mice exposed to high-dose total body irradiation (TBI). Mice were exposed to 0, 700, or 950 cGy TBI and subsequently received daily intravenous MSC-EV injections (1 × 10⁹ particles) for 3 days postirradiation. We evaluated survival rates, peripheral blood recovery, bone marrow engraftment, and bone marrow gene expression profiles at various intervals following treatment. MSC-EV administration significantly enhanced survival, with 70% of treated mice surviving 120 days after 950 cGy TBI exposure, compared with 0% survival in untreated controls by day 30. Although early peripheral blood recovery was not observed within 14 days, MSC-EV treatment facilitated substantial recovery at 3 months postirradiation, with significant increases in red blood cell, platelet, white blood cell, and hemoglobin levels, despite white blood cell and hemoglobin levels remaining slightly below normal. Furthermore, the engraftment capacity of bone marrow stem cells was significantly improved. The changes in hematopoietic-related gene expression presented at 14 days postirradiation returned to normal levels by 120 days in MSC-EV-treated mice. These results highlight the potential of MSC-EVs as a therapeutic strategy for high-dose radiation injuries by promoting hematopoietic recovery and improving survival. Our future research will focus on elucidating the radioprotective mechanisms and investigating their integration with existing therapies.