Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy; Duke Cancer Institute, Duke University, Durham, North Carolina.
Department of Radiation Oncology.
Int J Radiat Oncol Biol Phys. 2023 Aug 1;116(5):1163-1174. doi: 10.1016/j.ijrobp.2023.02.007. Epub 2023 Feb 14.
Victims of acute radiation exposure are susceptible to hematopoietic toxicity due to bone marrow damage and loss of mature blood elements. Here, we evaluated cord blood-derived endothelial progenitor cells (CB-EPCs) as a potential cellular therapy for mitigation of hematologic acute radiation syndrome. CB-EPCs express endothelial cell markers and maintain their growth characteristics beyond 10+ passages without diminishing their doubling capacity. Further, CB-EPCs can be cryopreserved in vapor-phase liquid nitrogen and easily recovered for propagation, making them an attractive nonimmunogenic cellular therapy for off-the-shelf use. Importantly, we show CB-EPCs have the capacity to potently expand adult human bone marrow hematopoietic progenitor cells both in vitro and in vivo.
To demonstrate the role of CB-EPCs in promoting in vivo human immune reconstitution after irradiation, we employed a novel humanized mouse model established by transplant of CD34 bone marrow cells from 9 unique adult organ donors into immunocompromised NSG-SGM3 mice. The response of the humanized immune system to ionizing irradiation was then tested by exposure to 1 Gy followed by subcutaneous treatment of CB-EPCs, Food and Drug Administration-approved growth factor pegfilgrastim (0.3 mg/kg), or saline.
At day 7, total human bone marrow was decreased by 80% in irradiated controls. However, treatment with either growth factor pegfilgrastim or CB-EPCs increased recovery of total human bone marrow by 2.5-fold compared with saline. Notably, CB-EPCs also increased recovery of both human CD34 progenitors by 5-fold and colony-forming capacity by 3-fold versus saline. Additionally, CB-EPCs promoted recovery of endogenous bone marrow endothelial cells as observed by both increased vessel area and length compared with saline.
These findings indicate the feasibility of using humanized mice engrafted with adult bone marrow for radiation research and the development of CB-EPCs as an off-the-shelf cellular therapy for mitigation of hematologic acute radiation syndrome.
由于骨髓损伤和成熟血液成分的丧失，急性辐射暴露的受害者易患造血毒性。在这里，我们评估了脐血衍生的内皮祖细胞（CB-EPC）作为减轻血液急性辐射综合征的潜在细胞治疗方法。CB-EPC 表达内皮细胞标志物，并在超过 10 个传代后保持其生长特性，而不会降低其倍增能力。此外，CB-EPC 可以在气相液氮中冷冻保存，并易于回收进行繁殖，使其成为一种有吸引力的非免疫细胞治疗方法，可用于现货使用。重要的是，我们表明 CB-EPC 具有在体外和体内有力扩增成人骨髓造血祖细胞的能力。
为了证明 CB-EPC 在促进照射后体内人类免疫重建中的作用，我们采用了一种通过将来自 9 个独特成年供体的 CD34 骨髓细胞移植到免疫缺陷型 NSG-SGM3 小鼠中建立的新型人源化小鼠模型。然后通过暴露于 1 Gy 来测试人源化免疫系统对电离辐射的反应，然后皮下给予 CB-EPC、食品和药物管理局批准的生长因子培非格司亭（0.3 mg/kg）或生理盐水。
在照射对照中，第 7 天，总人类骨髓减少了 80%。然而，与生理盐水相比，用生长因子培非格司亭或 CB-EPC 治疗可使总人类骨髓的恢复增加 2.5 倍。值得注意的是，CB-EPC 还使人类 CD34 祖细胞的恢复增加了 5 倍，集落形成能力增加了 3 倍，而生理盐水则增加了 3 倍。此外，与生理盐水相比，CB-EPC 还促进了内源性骨髓内皮细胞的恢复，表现为血管面积和长度均增加。
这些发现表明，用人骨髓移植的人源化小鼠进行辐射研究以及将 CB-EPC 开发为减轻血液急性辐射综合征的现货细胞治疗方法是可行的。
