MSC Exosome Treatment for BPD: Impact on Immunity and Lung Development

MSC 外泌体治疗 BPD：对免疫和肺部发育的影响

基本信息

批准号：
10359700
负责人：
Stella Kourembanas
金额：
$ 77.26万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359700
关键词：
Adoptive Transfer Adult Alveolar Alveolus Animal Disease Models Anti-Inflammatory Agents Biodistribution Biogenesis Biological Biological Assay Biological Process Blood Vessels Bronchopulmonary Dysplasia Cell Communication Cell Therapy Cells Chronic lung disease Complex Complication Disease Disease model Dose Dysbarism Endothelium Enrollment Epithelial Exhibits Experimental Models Fibrosis Glucocorticoids Goals Growth Growth and Development function Health Homeostasis Human Hyperoxia Immunity In Vitro Incidence Infection Inflammation Injury Lipid Bilayers Lipids Lung Lung diseases Mechanical ventilation Mediating Mediator of activation protein Mesenchymal Mesenchymal Stem Cells Methods Modeling Modernization Molecular Morbidity - disease rate Neonatal Hyperoxic Injury Neurological outcome Nonesterified Fatty Acids Nucleic Acids Pathogenesis Pathway interactions Phenotype Physiological Pre-Clinical Model Premature Birth Premature Infant Preparation Prevention Prevention strategy Proteins Proteomics Pulmonary Emphysema Pulmonary Hypertension Pulmonary Inflammation Pulmonary function tests RNA Reagent Reporting Risk Role Signal Pathway Signal Transduction Stromal Cells Structure Surface System Test Result Testing Therapeutic Therapeutic Effect Untranslated RNA Vesicle airway hyperresponsiveness base biophysical properties body system cell type density effective therapy exosome extracellular vesicles healing immunoregulation in vivo in vivo imaging intercellular communication lung development lung injury macrophage monocyte mortality mouse model multipotent cell neonatal mice neonatal period novel novel therapeutic intervention oxygen toxicity postnatal preconditioning premature prevent pulmonary function receptor stem stem cell exosomes stem cell therapy stem cells submicron systemic inflammatory response tool translational approach uptake vector ventilation

项目摘要

ABSTRACT Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease of preterm infants. With no single effective therapy for either the prevention or treatment of BPD, the need for new tools to treat and reduce risk of further complications associated with extreme preterm birth is urgent. Indeed, mesenchymal stromal/stem cell (MSC) therapy had shown promise in preclinical models of BPD, however more recent studies have established that the main therapeutic vectors of MSCs is comprised in their secretome and represented by exosomes. Exosomes are submicron, lipid bilayer-enclosed extracellular vesicles (EVs) expressed by most cells. Their varied origin, biogenesis and molecular composition enroll them in diverse and potent physiological roles, the most intriguing of which is an effective method of cell-to-cell communication. The MSC exosome composition has been reported to include small noncoding RNAs, free fatty acids, surface receptors and proteins, serving as vectors of MSC therapeutic effects. Consequently, in addition to their diverse roles in health and disease, exosomes represent novel reagents for therapeutic applications. We isolated exosomes from human MSC conditioned media, termed MEx, and showed that they inhibit BPD in the neonatal hyperoxia mouse model. Specifically, one dose of Mex inhibits lung inflammation, alveolar injury, pulmonary hypertension, fibrosis, and normalizes long-term lung function. We have demonstrated that MEx are taken up by macrophages (Mφs) and, as result, shift the Mφ phenotype to inflammation resolving, antifibrotic, and anti- remodeling. We hypothesize that Mφs are key vectors of MEx therapeutic action, orchestrating cell-to-cell communication signals to promote normal alveogenesis and to restore lung homeostasis. We will test this hypothesis in the following specific aims: SA#1: To isolate and comprehensively characterize MEx subpopulations and investigate mechanisms of their action and biological potency in vitro and in vivo; SA#2: To test the role of monocytes/Mφs as mediators of MEx signals to lung cells; SA#3: To investigate the biologic function of monocytes/Mφs, modified by MEx, on hyperoxia-induced BPD in vivo.

抽象的支气管肺发育不良（BPD）是早产儿的一种多因素慢性肺部疾病。预防或治疗 BPD 的有效疗法，需要新的工具来治疗和降低风险事实上，间充质基质/干细胞与极端早产相关的进一步并发症迫在眉睫。细胞 (MSC) 疗法在 BPD 的临床前模型中显示出前景，但最近的研究表明确定 MSC 的主要治疗载体包含在其分泌组中，并由外泌体是大多数细胞表达的亚微米、脂质双层封闭的细胞外囊泡 (EV)。它们不同的起源、生物发生和分子组成使它们具有多样化和有效的生理功能。 MSC 外泌体具有多种作用，其中最有趣的是细胞间通讯的有效方法。据报道，其成分包括小非编码 RNA、游离脂肪酸、表面受体和蛋白质，除了它们在中的不同作用外，还作为 MSC 治疗效果的载体进行测试。健康和疾病，外泌体代表了用于治疗应用的新型试剂。来自人类 MSC 条件培养基，称为 MEx，并表明它们可以抑制新生儿高氧血症中的 BPD 具体来说，一剂 Mex 可以抑制肺部炎症、肺泡损伤、肺部炎症。高血压、纤维化，并使长期肺功能正常化我们已经证明 MEx 被吸收。巨噬细胞 (Mφs) 的作用，因此将 Mφ 表型转变为消炎、抗纤维化和抗- 我们勇敢地承认 Mφ 是 MEx 治疗作用的关键载体，协调细胞间的作用。促进正常肺泡发生并恢复肺稳态的通讯信号我们将对此进行测试。 SA#1：分离并全面表征 MEx 亚群并研究其体外和体内的作用机制和生物效力；SA#2；测试单核细胞/Mφ 作为肺细胞 MEx 信号介质的作用：研究生物学；由MEx修饰的单核细胞/Mφs对体内高氧诱导的BPD的功能。