Exosome educated monocytes for acute radiation syndrome

外泌体训练的单核细胞治疗急性放射综合征

• 批准号: 10458706
• 负责人: Christian Capitini
• 金额: $ 52.53万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458706
• 关键词: Allogeneic Bone Marrow Transplantation; Allogenic; Anemia; Animal Model; Biomanufacturing; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Bone marrow failure; CD34 gene; CXCR4 gene; Cell Survival; Cell Therapy; Cells; Coculture Techniques; Collaborations; DNA; Development; Engineering; Exposure to; Flow Cytometry; Generations; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Histopathology; Hour; Human; Immune; Immunodeficient Mouse; Individual; Infection; Infusion procedures; Interleukin-6; Label; Lead; Life; Lipopolysaccharides; Magnetic Resonance Imaging; Mediating; Medical; Membrane; Mesenchymal Stem Cells; MicroRNAs; Modeling; Mus; National Security; Neonatal; Organ; Patients; Population; Pre-Clinical Model; Procedures; Production; RNA; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation Protection; Radiation Tolerance; Radiation Toxicity; Radiation exposure; Radiation therapy; Recovery; Risk; Role; Signal Transduction; System; TLR4 gene; Terrorism; Testing; Thymus Gland; Toxic effect; Translations; Vesicle; Whole-Body Irradiation; clinical practice; cytokine; exosome; high risk; humanized mouse; improved; in vivo; innovation; insight; interest; macrophage; mesenchymal stromal cell; mimetics; monocyte; mortality risk; mouse model; novel therapeutics; radiation effect; stem cell exosomes; stem cell proliferation; success; therapy development; trafficking

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.

项目总结/摘要 寻找治疗辐射诱导的毒性的新疗法不仅对受辐射影响的患者有价值， 接受放射治疗的条件不同，而且由于恐怖主义袭击的风险，国家安全。 迫切需要开发在暴露后可以快速施用的疗法，以最小化暴露后的并发症。 辐射的影响和增强免疫力的恢复。临床前模型已经为我们提供了大量的信息， 急性放射综合征（ARS）的临床治疗现状。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，对其进行工程改造， 细胞因子，并了解细胞如何与其他造血和免疫细胞在体内相互作用后， 输注都是开发用于ARS的适当的基于细胞的疗法的关键因素。我们的团队以前 其特征在于一种交替活化的、高IL-6产生的人巨噬细胞亚群，称为间充质细胞， 干细胞（MSC）训练的巨噬细胞，可以使用异种小鼠提高致死ARS的存活率 与单独的MSC或巨噬细胞输注相比，我们已经简化了这些细胞的生成 通过使用来自脂多糖刺激的MSC的外来体将单核细胞培养成辐射防护细胞 子集该提案的长期目标是使用MSC-外泌体来改善MSC-外泌体的产生， 放射防护细胞的功效，并确定其在ARS临床前模型中的放射防护机制。我们 （1）LPS-高外泌体训练的单核细胞（LPS-高EEMos）可以介导 通过产生IL-6作为同种异体细胞疗法的辐射防护;（2）LPS-高EEMos保护宿主 通过运输到辐射敏感器官，如骨髓，从ARS，并可以通过磁共振跟踪 成像（MRI）;和（3）LPS模拟物可用于刺激MSC外泌体产生， 通过let-7 b microRNA分泌。任何一个目标的成功都将是一个重大的进步， 了解单核细胞如何影响ARS后的血细胞发育。整个提案的翻译将 导致对治疗ARS的新细胞疗法的创新的、机械的理解。