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

摘要 摘要支气管肺发育不良(Bpd)是早产儿最常见的并发症，其发病率较高。 升高与极早产儿存活率增加有关。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造成的 氧气暴露、感染和机械通气。炎症是一条重要的致病途径 BPD的发病机制，可导致重大的长期多系统疾病，包括不良 神经学转归、易受感染的免疫失调和肺部疾病 包括哮喘，在某些情况下，肺气肿的变化会持续到成年。因此，bpd不是 不再被认为是新生儿期的肺部疾病，但这是一种复杂的多器官受累情况 以及终生后果。到目前为止，缺乏有效的治疗方法，需要提供有效的 预防和管理bpd的战略。骨髓间充质干细胞(MSCs)的临床应用 作为治疗bpd的潜在细胞疗法的试验。我们和其他人已经证明，治疗的主要方式是 MSCs驻留在它们的分泌体中，以细胞外小泡(SEV)为代表，SEV是EV的一个子集， 包括外体。我们证明了用纯化的人骨髓间充质干细胞衍生的SEV治疗，称为MEX， 改善甚至逆转BPD的几个实验性核心组织学和功能结果 模特们。在新生儿高氧(HYRX)小鼠BPD模型中，MEX保护其他器官免受损伤 包括大脑、视网膜和胸腺，它们的结构被HYRX破坏了。我们证明了这一点 MEX定位于肺，并与髓系细胞相互作用，使其表型从促炎变为 免疫抑制。重要的是，体外过继移植Mex教育的骨髓来源的髓系细胞 细胞，而不是幼稚的细胞，恢复了肺泡结构，钝化的纤维化和血管重塑，以及 提高运动能力。我们假设MEX调节发育中的肺的免疫格局 促进一种独特的巨噬细胞表型，通过释放抗炎细胞因子和 增强凋亡细胞的吞噬作用，化解组织炎症，并协调信号以促进 HYRX干扰了肺的生长。在这项提案中，我们计划(1)阐明墨西哥促进 肺泡巨噬细胞生态位的建立和天然免疫的发展 新生儿HYRX；(2)探索MEX介导的肺髓系细胞在消炎中的功能 和促进肺发育；以及(3)阐明新生儿HYRX和Mex治疗对Long 长期免疫细胞功能与呼吸道疾病的易感性。

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.