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：
10586246
负责人：
Stella Kourembanas
金额：
$ 88.49万
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 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586246
关键词：
Adoptive Transfer Adult Affect Airway Disease Alveolar Alveolar Macrophages Anti-Inflammatory Agents Apoptotic Architecture Asthma Biological Bone Marrow Brain Bronchopulmonary Dysplasia Cell Therapy Cell physiology Cells Clinical Trials Complex Complication Development Disease Etiology Experimental Models Fibrosis Goals Growth Histologic Human Hyperoxia Immune Immunity In Vitro Incidence Infection Inflammation Inflammatory Injury Life Lung Lung diseases Macrophage Mechanical ventilation Mediating Mesenchymal Modality Modeling Molecular Morbidity - disease rate Mus Myelogenous Myeloid Cells Natural Immunity Neonatal Hyperoxic Injury Neurological outcome Organ Oxygen Pathogenesis Pathway interactions Perinatal Phenotype Population Pre-Eclampsia Predisposition Premature Birth Prevention strategy Pulmonary Emphysema Pulmonary Inflammation Research Retina Role Signal Pathway Signal Transduction Stromal Cells Structure of thymic medulla System T-Cell Development Testing Therapeutic Thymus Gland Tissues Vascular remodeling adaptive immunity airway hyperresponsiveness airway inflammation cytokine effective therapy exercise capacity exosome experimental study extracellular vesicles extreme prematurity functional outcomes hyperoxia induced lung injury immune function immunoreactivity improved in vivo injury and repair intraamniotic infection lung development mesenchymal stromal cell monocyte neonatal period organ injury premature prenatal risk factor programs protective effect recruit stem systemic inflammatory response translational approach vector

项目摘要

Abstract Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity whose incidence is on the rise associated with the increased survival of extremely preterm infants. The etiology of BPD is multifactorial resulting from prenatal risk factors such as preeclampsia, chorioamnionitis, and perinatal insults including oxygen exposure, infection, and mechanical ventilation. Inflammation is a key pathway underlying the pathogenesis of BPD which can result in significant long-term multisystem morbidities, including adverse neurological outcomes, immune dysregulation with susceptibility to infections, and pulmonary morbidities including asthma and, in some cases, emphysematous changes that persist into adulthood. Thus, BPD is no longer considered a lung disease of the neonatal period, but a complex condition with multiorgan involvement and lifelong consequences. To date, effective treatments are lacking and there is a need to deliver effective strategies for the prevention and management of BPD. Mesenchymal stem/stromal cells (MSCs) are in clinical trials as potential cellular therapy for BPD. We and others have shown that the main therapeutic modality of MSCs resides in their secretome represented by `small' extracellular vesicles (sEVs), an EV subset that includes exosomes. We demonstrated that treatment with purified human MSC-derived sEvs, termed MEx, ameliorated and even reversed core histological and functional outcomes of BPD in several experimental models. In the neonatal hyperoxia (HYRX) murine BPD model, MEx protected other organs from injury including the brain, retina, and the thymus whose architecture was disrupted by HYRX. We demonstrated that MEx localize in the lung and interact with myeloid cells altering their phenotype from proinflammatory to immunosuppressive. Importantly, adoptive transfer of in vitro MEx-educated bone marrow derived myeloid cells, but not naïve cells, restored alveolar architecture, blunted fibrosis and vascular remodeling, and improved exercise capacity. We hypothesize that MEx regulate the immune landscape of the developing lung and promote a distinct macrophage phenotype that, through release of anti-inflammatory cytokines and enhanced efferocytosis of apoptotic cells, resolves tissue inflammation and orchestrates signals to promote lung growth disrupted by HYRX. In this proposal we plan to (1) Elucidate mechanisms by which MEx promote the establishment of the alveolar macrophage niche and development of innate immunity that is disrupted by neonatal HYRX; (2) Explore the functionality of lung myeloid cells instructed by MEx in resolving inflammation and promoting lung development; and (3) Elucidate the effects of neonatal HYRX and MEx treatment on long term immune cell function and susceptibility to airway disease.

抽象的支气管肺发育不良（BPD）是早产儿最常见的并发症，其发病率在 BPD 的病因是多因素的。由先兆子痫、绒毛膜羊膜炎和围产期侮辱等产前危险因素引起，包括氧气暴露、感染和机械通气是潜在的关键途径。 BPD 的发病机制可能导致严重的长期多系统发病，包括不良反应神经系统结果、易受感染的免疫失调和肺部疾病包括哮喘，以及在某些情况下持续到成年的肺气肿变化，因此，BPD 不是疾病。不再被认为是新生儿期的肺部疾病，而是一种涉及多器官的复杂疾病迄今为止，缺乏有效的治疗方法，因此需要提供有效的治疗。预防和管理 BPD 的策略已进入临床。我们和其他人已经证明，BPD 的主要治疗方式是细胞疗法。 MSC 存在于以“小”细胞外囊泡 (sEV) 为代表的分泌蛋白组中，sEV 是一种 EV 子集，我们证明，用纯化的人 MSC 衍生的 sEv（称为 MEx）进行治疗，在一些实验中改善甚至逆转了 BPD 的核心组织学和功能结果在新生儿高氧 (HYRX) 小鼠 BPD 模型中，MEx 可以保护其他器官免受损伤。包括大脑、视网膜和胸腺，其结构被 HYRX 破坏。 MEx 定位于肺部并与骨髓细胞相互作用，将其表型从促炎性改变为重要的是，体外 MEx 教育的骨髓来源的骨髓的过继转移。细胞，但不是幼稚细胞，恢复了肺泡结构，减弱了纤维化和血管重塑，并且我们认为 MEx 可以调节发育中的肺部的免疫环境。并促进独特的巨噬细胞表型，通过释放抗炎细胞因子和增强凋亡细胞的胞吞作用，解决组织炎症并协调信号以促进 HYRX 扰乱肺部生长在本提案中，我们计划 (1) 阐明 MEx 促进的机制。肺泡巨噬细胞生态位的建立和先天免疫的发展被破坏新生儿HYRX；（2）探索MEx指导肺髓细胞解决炎症的功能促进肺部发育；(3) 阐明新生儿 HYRX 和 MEx 治疗对长期的影响术语免疫细胞功能和对气道疾病的易感性。