Mechanisms of immunomodulation in lung injury by mesenchymal stromal cell exosomes

间充质基质细胞外泌体对肺损伤的免疫调节机制

• 批准号: 9891564
• 负责人: Gareth Rhys Willis
• 金额: $ 10.8万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2020-10-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891564
• 关键词: Alveolar; Anti-Inflammatory Agents; Biochemical; Biodistribution; Biogenesis; Biological Assay; Biological Process; Biology; Biophysics; Blood Vessels; Bolus Infusion; Bronchopulmonary Dysplasia; Cardiac; Cell Communication; Cell Therapy; Cells; ChIP-seq; Chronic; Chronic lung disease; Coculture Techniques; Complex; Complication; Coupled; Data; Development; Disease; Dose; Endothelial Cells; Epigenetic Process; Epithelial Cells; Experimental Models; Growth; Health; Histologic; Human; Hyperoxia; Impairment; In Vitro; Incidence; Inflammatory; Injury; Investigation; Investigational Therapies; Lipids; Lung; Lung diseases; Mechanical ventilation; Mediating; Mesenchymal; Microscopic; Modality; Modeling; Molecular; Morphology; Outcome; Oxygen Therapy Care; Pharmacotherapy; Phase; Phenotype; Population; Pre-Clinical Model; Premature Infant; Prevention; Production; Property; Proteins; Proteomics; Pulmonary Fibrosis; Pulmonary Hypertension; RNA; Reporter; Respiratory physiology; Risk; Role; Signal Transduction; Stromal Cells; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Treatment Efficacy; Umbilical cord structure; United States; Untranslated RNA; Vascular remodeling; Vesicle; base; biophysical properties; blood vessel development; effective therapy; epigenome; exosome; extracellular vesicles; hemodynamics; immunoregulation; improved; in vivo; in vivo imaging; insight; lung development; lung injury; macrophage; mesenchymal stromal cell; mouse model; neonatal period; novel; novel therapeutics; postnatal; preterm newborn; prevent; pulmonary function; stem; submicron; success; tool; vector

Summary With no single effective therapy for either the prevention or treatment of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants, the need for new tools to treat and reduce risk of further complication is urgent. Mesenchymal stem/stromal cell (MSC) therapy has shown promise in preclinical models of BPD, demonstrating both histological and functional benefits. We have shown that the therapeutic capacity of MSCs is comprised in their secretome, and that the major therapeutic vector therein is represented by the exosomes. Exosomes are submicron vesicles that harbor a diverse array of bioactive cargo (e.g. lipids, diverse proteins, and small non-coding RNAs). Recently, using a murine model of hyperoxia-induced BPD, we demonstrated that a bolus dose of human MSC-exosomes (termed MEx), significantly improved lung morphology, pulmonary development and lung function, decreased lung fibrosis, restored pulmonary blood vessel loss and ameliorated pulmonary vascular remodeling and pulmonary hypertension. We have also demonstrated that MEx are readily taken up by macrophages (Mφ) both in vitro and in vivo and, as a result, shift the Mφ phenotype to an anti- inflammatory, anti-fibrotic, and pro-regulatory state. However, despite the promising therapeutic potential of MEx, our understanding of their bioactive properties and the molecular mechanism(s) responsible for such effects remain unclear. Exosomes are a heterogeneous EV population. Exosome subpopulations are known to differ in biophysical, proteomic and RNA repertoire. Consequently, different MEx subsets mediate alternative biological functions. In this proposal we predict that only a certain subtype of MEx is responsible for the therapeutic effects, and that this ‘bioactive’ MEx subset dampens inflammatory signaling in the lung via modulation of Mφ phenotype and prevents the development of hyperoxia–induced vascular and alveolar injury. To test these hypotheses, we propose the following specific aims (SA). SA#1: To isolate, characterize and define therapeutic (‘bioactive’) MEx subsets. SA#2: To assess MEx in vivo biodistribution and anti-inflammatory/immunomodulatory capacity. SA#3: Investigate how MEx impacts the epigenetic landscape of target cells in our experimental BPD model. Collectively, this proposal will provide important insights in MEx biology and MEx-target cell interaction, that can be leveraged to develop effective, novel therapeutic modalities for BPD.

摘要 由于没有预防或治疗支气管肺发育不良(BPD)的单一有效疗法，a 对于早产儿的慢性肺部疾病，需要新的工具来治疗和降低进一步并发症的风险 很紧急。间充质干细胞/基质细胞(MSC)治疗在BPD的临床前模型中显示出良好的前景， 显示出组织和功能上的益处。我们已经证明，骨髓间充质干细胞的治疗能力 由它们的分泌体组成，而其中的主要治疗载体由外泌体代表。 外切体是含有多种生物活性物质(例如，脂类，不同蛋白质， 和小的非编码RNA)。最近，使用高氧诱导的BPD小鼠模型，我们证明了 一剂人MSC-exosome(称为MEX)，显著改善肺形态，肺 发展和肺功能，减少肺纤维化，恢复肺血管的损失和改善 肺血管重构与肺动脉高压。我们还证明了墨西哥很容易 在体外和体内都被巨噬细胞(Mφ)摄取，结果将Mφ的表型转变为抗 炎症、抗纤维化和支持调节的状态。然而，尽管Mex有很好的治疗潜力， 我们对它们的生物活性及其分子机制的了解(S) 目前仍不清楚。Exosome是一个异质性的EV群体。已知的外体亚群在 生物物理学、蛋白质组学和核糖核酸谱。因此，不同的MEX子集中介了另一种生物 功能。在这项建议中，我们预测只有特定亚型的MEX对治疗效果负责， 这种具有生物活性的MEX亚群通过调节M-φ的表型来抑制肺部的炎症信号 并防止高氧性血管和肺泡损伤的发展。为了检验这些假设，我们 提出以下具体目标(SA)。SA#1：分离、鉴定和定义治疗性(生物活性)Mex 子集。SA#2：评估Mex在体内的生物分布和抗炎/免疫调节能力。SA#3： 在我们的实验性BPD模型中，研究MEX如何影响目标细胞的表观遗传格局。 总的来说，这项提议将在墨西哥生物学和墨西哥-靶细胞相互作用方面提供重要的见解，这可以 将被用来开发有效的、新的BPD治疗方法。