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

炎症是身体对感染、刺激或其他损伤的反应方式。通常，炎症是身体愈合和应对感染的一种方式，然而，当在某些情况下如败血症中失调时，它可能导致严重损伤和损害器官功能。近年来，越来越多的临床医生和基础科学家的注意力被吸引到基于细胞的治疗。与药物治疗相比，基于细胞的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种损伤和修复途径。基于细胞的治疗的最有前途的候选者之一是称为间充质干细胞（MSC）的细胞，它代表一种成体干细胞（可以很容易地从成年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。骨髓间充质干细胞可以很容易地在实验室条件下繁殖和操作，并有能力分化成不同的细胞类型的身体。重要的是，长期研究表明，它们在发展肿瘤方面是安全的。我们小组和其他研究人员进行的多项临床前动物研究表明，MSC在治疗炎症时确实具有保护作用。在几种有益的效果中，它们的施用总是与炎症的急剧减少有关，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MSC转化为临床实践，我们必须更准确地了解其作用机制。在这项研究中，我们正在寻求建立MSC对真正的生理炎症环境的反应。我们已经建立了体外模型的原代人类细胞刺激的样品从正在进行的临床试验，作为最生理相关的模拟炎症microenvironment.In这个项目中，我们将调查的新机制，MSC效应介导的能力，这些细胞释放小膜包裹的“细胞外囊泡”。我们特别感兴趣的是那些含有调控分子的囊泡，称为miRNAs。在确定通过细胞外囊泡将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，通过分析进入我们的MSC治疗ARDS临床试验的患者的临床样本来验证我们对MSC治疗效果的研究结果。原则预期的输出是建立MSC细胞治疗的免疫调节作用的明确和强大的机制，为MSC和MSC衍生的细胞外囊泡的进一步试验提供信息。这些发现还将为细胞制造目的的效价测定提供信息，并为未来的MSC工程提供见解，以提高其治疗效果。这项研究的机制数据将使MSC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.