Wen Sicheng, Dooner Mark, Pereira Mandy, Del Tatto Michael, Quesenberry Peter
Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, Rhode Island, USA.
Stem Cells Dev. 2025 May;34(9-10):189-200. doi: 10.1089/scd.2025.0036. Epub 2025 Mar 26.
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 × 10 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.
暴露于高剂量辐射通常会导致造血急性放射综合征，导致早期死亡，而目前针对暴露于致死性辐射剂量患者的治疗方法有限。间充质干细胞衍生的细胞外囊泡（MSC-EVs）在组织修复和再生方面显示出前景，但在减轻高剂量辐射损伤方面尚未得到充分研究。我们之前证明，人或小鼠的MSC-EVs可以逆转轻度或中度辐射引起的骨髓损伤。当前研究评估了人MSC-EVs对接受高剂量全身照射（TBI）小鼠的治疗潜力。小鼠接受0、700或950 cGy的TBI，随后在照射后3天每天静脉注射MSC-EV（1×10个颗粒）。我们在治疗后的不同时间间隔评估了存活率、外周血恢复情况、骨髓植入情况以及骨髓基因表达谱。给予MSC-EV显著提高了存活率，950 cGy TBI照射后，70%接受治疗的小鼠存活至120天，而未治疗的对照组在第30天时存活率为0%。虽然在14天内未观察到早期外周血恢复，但MSC-EV治疗在照射后3个月促进了大量恢复，红细胞、血小板、白细胞和血红蛋白水平显著升高，尽管白细胞和血红蛋白水平仍略低于正常水平。此外，骨髓干细胞的植入能力显著提高。照射后14天出现的造血相关基因表达变化在接受MSC-EV治疗的小鼠中到120天时恢复到正常水平。这些结果突出了MSC-EVs作为高剂量辐射损伤治疗策略的潜力，即通过促进造血恢复和提高存活率来发挥作用。我们未来的研究将集中于阐明辐射防护机制，并研究它们与现有疗法的整合。
