"The role of extracellular vesicle miRNAs in Mesenchymal Stem Cells' effects on macrophage modulation in ARDS"

炎症是身体对感染、刺激或其他伤害的反应方式。正常情况下，炎症是身体修复和应对感染的一种方式，然而，当在某些情况下，如败血症时，炎症可能会导致严重的损害和器官功能的损害。近年来，细胞治疗受到越来越多的临床医生和基础科学家的关注。与药物治疗相比，细胞治疗的一个关键优势是细胞可以主动响应局部微环境并发挥多种有益作用，调节复杂疾病过程中的几条损伤和修复途径。细胞治疗最有希望的候选细胞之一是间充质干细胞(MSCs)，它代表一种成体干细胞(可以很容易地从成人患者或健康志愿者的组织中分离出来)，因此，不存在伦理问题。MSCs可以在实验室条件下很容易地繁殖和操作，并具有分化为身体不同细胞类型的能力。重要的是，长期的研究已经证明了它们在发展肿瘤方面的安全性。我们小组以及其他研究人员进行的多项临床前动物研究表明，当MSCs作为一种炎症条件的治疗时，确实具有保护作用。在许多有益的作用中，它们的使用总是与显著减少炎症有关，然而这种现象的机制仍然不清楚，关于它们与免疫细胞相互作用的数据仍然不充分和有争议。为了将MSCs转化为临床实践，我们必须对其作用机制有更准确的了解。在这项研究中，我们试图建立MSCs对真实的生理性炎症环境的反应。我们已经建立了从正在进行的临床试验中获得的患者样本刺激的原代人类细胞的体外模型，作为与生理上最相关的炎性微环境的模拟。在这个项目中，我们将研究MSC效应的新机制，该机制是通过这些细胞释放包裹在细胞外的小囊泡的能力来实现的。我们对含有调控分子的小泡特别感兴趣，称为miRNA。在确定了通过细胞外小泡将miRNA转移到原代人类细胞的重要性后，我们将在动物模型中验证我们的发现。最后，我们有一个独特的机会来验证我们关于MSC治疗有效性的发现，方法是分析参与我们对MSCs进行ARDS临床试验的患者的临床样本。预期的原则是建立一种明确和强大的MSC细胞治疗免疫调节作用的机制，为进一步的MSCs和MSC来源的细胞外小泡试验提供信息。这些发现还将为用于细胞制造目的的效力分析提供信息，并为未来的骨髓间充质干细胞工程提供见解，以提高其治疗效率。本研究的机制数据将使骨髓间充质干细胞更接近患者。

Inflammation is the way in which the body reacts to infection, irritation or other injury. Normally, inflammation is one way the body heals and copes with the infection, However, when dysregulated in certain condition such as sepsis it can lead to severe damage and impair organ function. Recently more and more clinicians and basic scientists attention is drawn to cell-based therapies. A key advantage of cell based therapy compared to pharmacologic treatment is that cells can actively respond to the local microenvironment and exert multiple beneficial effects, modulating several injurious and reparative pathways in complex disease process.One of the most promising candidate for a cell based therapy are cells termed Mesenchymal Stem Cells (MSCs), which represent one kind of adult stem cells (can be easily isolated from tissues of adult patients or healthy volunteers), because of this, there is no ethical issues. MSCs could easily be propagated and manipulated under laboratory conditions and have capacity to differentiate into different cell types of the body. Importantly, long term research has shown their safety in terms of developing tumors.Multiple preclinical animal studies conducted by our group as well as by other investigators showed that MSCs indeed have protective effect when administered as a treatment for inflammatory conditions. Among several beneficial effects, their administration always is associated with drastically reduced inflammation, however the mechanisms of this phenomenon are still unclear and data on their interaction with the immune cells remain unsufficient and controversial. To translate MSCs into the clinical practice it is essential that we have more precise understanding of their mechanism of action. In this study we are seeking to establish the MSCs' response to a true physiological inflammatory environment. We have established in vitro models of primary human cells stimulated with samples from patients available from ongoing clinical trials, as the most physiologycally relevant mimic of inflammatory microenvironment.In this project we will investigate the novel mechanism of MSC effect mediated through the capacity of these cells to release small membrane wrapped "exracellular vesicles". We are specifically interested in those vesicles which contain regulatory molecules, termed miRNAs.After establishing the importance of miRNA transfer via extracellular vesicles to the primary human cells we will validate our findings in the animal model. Finally we have a unique opportunity to validate our findings on MSC therapeutic efficacy by analysing clinical samples of patients who had entered into our clinical trial for MSCs in ARDS.The principle anticipated output is the establishment of a defined and robust mechanism of immunomodulatory action of MSC cell therapy which inform further trials for MSCs and MSC-derived extracellular vesicles. These findings will also inform potency assays for cell manufacturing purposes and provide insights into future MSC engineering to improve their therapeutic efficacy.The mechanistic data from this study will bring MSCs closer to the patient.