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

“细胞外囊泡 miRNA 在间充质干细胞对 ARDS 巨噬细胞调节的影响中的作用”

• 批准号: MR/S009426/1
• 负责人: Anna Krasnodembskaya
• 金额: $ 72.23万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS009426%2F1
• 关键词: role; extracellular; vesicle; miRNAs; Mesenchymal

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.

炎症是身体对感染、刺激或其他伤害的反应。正常情况下，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，它会导致严重的损害和损害器官功能。近年来，细胞疗法越来越受到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积极响应局部微环境并发挥多种有益作用，在复杂的疾病过程中调节几种损伤和修复途径。其中最有希望的细胞治疗候选者是被称为间充质干细胞（MSCs）的细胞，它代表了一种成体干细胞（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。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类型的身体细胞。重要的是，长期研究表明，它们在产生肿瘤方面是安全的。我们小组以及其他研究者进行的多项临床前动物研究表明，MSCs在治疗炎症时确实具有保护作用。在几种有益作用中，它们的施用总是与炎症的急剧减少有关，然而这一现象的机制尚不清楚，它们与免疫细胞相互作用的数据仍然不充分和有争议。为了将间充质干细胞转化为临床实践，我们必须对其作用机制有更精确的了解。在这项研究中，我们试图建立间充质干细胞对真实生理炎症环境的反应。我们已经建立了体外原代人细胞模型，用来自正在进行的临床试验的患者样本刺激，作为最具生理学相关性的炎症微环境模拟。在这个项目中，我们将研究通过这些细胞释放小膜包裹的“细胞外囊泡”的能力介导间充质干细胞效应的新机制。我们特别感兴趣的是那些包含调控分子的囊泡，称为mirna。在确定miRNA通过细胞外囊泡转移到原代人细胞的重要性之后，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，通过分析参加我们的ARDS临床试验的MSCs患者的临床样本，来验证我们关于MSC治疗效果的发现。预期的主要成果是建立一个明确的和强大的间充质干细胞治疗免疫调节作用机制，为间充质干细胞和间充质干细胞衍生的细胞外囊泡的进一步试验提供信息。这些发现也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MSCs更接近患者。

项目成果

The Role of Lung Resident Mesenchymal Stromal Cells in the Pathogenesis and Repair of Chronic Lung Disease.

• DOI: 10.1093/stmcls/sxad014
• 发表时间: 2023-05-15
• 期刊: Stem cells (Dayton, Ohio)

Nebulised mesenchymal stem cell derived extracellular vesicles ameliorate E. coli induced pneumonia in a rodent model.

• DOI: 10.1186/s13287-023-03385-6
• 发表时间: 2023-06-06
• 期刊: STEM CELL RESEARCH & THERAPY
• 影响因子: 7.5
• 作者: Gonzalez, Hector;McCarthy, Sean;Masterson, Claire;Byrnes, Declan;Sallent, Ignacio;Horan, Emma;Elliman, Stephen J.;Vella, Gabriele;Mello, Adriele P.;Silva, Johnatas D.;Krasnodembskaya, Anna D.;MacLoughlin, Ronan;Laffey, John G.;O'Toole, Daniel
• 通讯作者: O'Toole, Daniel

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cell Administration (REALIST-COVID) Phase 2 Randomised Controlled Trial

通过基质细胞管理修复 COVID-19 中的急性呼吸窘迫综合征 (REALIST-COVID) 第 2 期随机对照试验

• DOI: 10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a5285
• 发表时间: 2022
• 作者: Gorman E

Multicomponent Peptide Hydrogels as an Innovative Platform for Cell-Based Tissue Engineering in the Dental Pulp.

多组分肽水凝胶是牙浆中基于细胞的组织工程的创新平台。

• DOI: 10.3390/pharmaceutics13101575
• 发表时间: 2021-09-28
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Afami ME;El Karim I;About I;Krasnodembskaya AD;Laverty G;Lundy FT
• 通讯作者: Lundy FT

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.

• DOI: 10.1152/ajplung.00218.2020
• 发表时间: 2020-12-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Abreu SC;Hampton TH;Hoffman E;Dearborn J;Ashare A;Singh Sidhu K;Matthews DE;McKenna DH;Amiel E;Barua J;Krasnodembskaya A;English K;Mahon B;Dos Santos C;Cruz FF;Chambers DC;Liu KD;Matthay MA;Cramer RA;Stanton BA;Rocco PRM;Wargo MJ;Weiss DJ;Rolandsson Enes S
• 通讯作者: Rolandsson Enes S