Exosome educated monocytes for acute radiation syndrome

项目摘要/摘要 寻找治疗辐射毒性的新疗法不仅对 接受放射治疗的条件不同，也有因国家安全受到恐怖袭击的风险。 迫切需要开发一种可以在暴露后迅速实施的治疗方法，以最大限度地减少 具有抗辐射和增强免疫功能的作用。临床前模型已经为我们的许多 目前治疗急性辐射综合征(ARS)的临床实践。这些模型可用于测试和 开发新的细胞疗法。选择合适的细胞子集，对其进行工程设计以生产所需的 细胞因子，以及了解细胞如何在体内与其他造血和免疫细胞相互作用 输液都是开发适当的基于细胞的ARS疗法的关键因素。我们小组之前已经 表征了一种交替激活的、高产生IL-6的人巨噬细胞亚群，称为间充质 干细胞(MSC)培养的巨噬细胞可以提高异种小鼠对致死性ARS的存活率 与单独输注骨髓间充质干细胞或巨噬细胞相比。我们已经简化了这些细胞的生成 利用脂多糖刺激的骨髓间充质干细胞的外切体将单核细胞培养成辐射防护细胞 子集。这项建议的长期目标是使用MSC-exosome来改善后代和 放射防护细胞在急性呼吸窘迫综合征临床前模型中的有效性及其放射防护机制的确定。我们 我将检验以下假设：(1)高外显子教育单核细胞(高内毒素EEMOS)可以介导 作为同种异体细胞治疗的辐射防护通过产生IL-6；(2)高内毒素的EEMO保护宿主 从ARS到辐射敏感的器官，如骨髓，可以通过磁共振进行追踪 成像(MRI)；以及(3)内毒素模拟物可以用来刺激产生EEMO的MSC外切体的产生 通过let-7b微RNA的分泌。任何个人目标的成功都将是对 了解单核细胞如何影响急性呼吸综合征后的血细胞发育。整个提案的翻译将 导致对治疗ARS的一种新的细胞疗法的创新和机理的理解。

PROJECT SUMMARY/ABSTRACT Finding novel therapies for treatment of radiation-induced toxicities is of value to not only patients who are receiving radiotherapy for different conditions, but also to national security due to risk of terrorism attacks. There is urgent need to develop therapies than can be administered quickly after exposure to minimize the effects of radiation and enhance immune recovery. Preclinical models have informed a great deal of our current clinical practice in managing acute radiation syndrome (ARS). These models can be used to test and develop new cellular therapies. Choosing the proper cell subset, engineering it to produce the necessary cytokines, and understanding how the cells interact with other hematopoietic and immune cells in vivo after infusion are all critical factors in developing a proper cell-based therapy for ARS. Our group has previously characterized an alternatively activated, high IL-6 producing human macrophage subset called mesenchymal stem cell (MSC)-educated macrophages that can enhance survival from lethal ARS using a xenogeneic mouse model as compared to infusions of MSCs or macrophages alone. We have simplified generation of these cells by using exosomes from lipopolysaccharide-stimulated MSCs to educate monocytes into a radioprotective cell subset. The long-term objectives of this proposal are to use MSC-exosomes to improve the generation and efficacy of radioprotective cells and define their mechanism of radioprotection in preclinical models of ARS. We will test the hypotheses that: (1) LPS-high exosome-educated monocytes (LPS-high EEMos) can mediate radioprotection as an allogeneic cell therapy through production of IL-6; (2) LPS-high EEMos protect the host from ARS by trafficking to radiosensitive organs, like bone marrow, and can be tracked by magnetic resonance imaging (MRI); and (3) LPS-mimetics can be used to stimulate MSC exosome production that generate EEMos through let-7b microRNA secretion. Success of any of the individual aims will be a major advance in understanding how monocytes impact blood cell development after ARS. Translation of the entire proposal will lead to an innovative, mechanistic understanding of a new cellular therapy for treating ARS.