"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.

炎症是人体对感染，刺激或其他损伤的反应方式。通常，炎症是人体愈合并应对感染的一种方式，但是，当在某些情况下（例如败血症）失调时，它会导致严重损害并损害器官功能。最近，越来越多的临床医生和基本科学家注意到基于细胞的疗法。 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这没有道德问题。在实验室条件下可以轻松地繁殖和操纵MSC，并具有分化为身体不同细胞类型的能力。重要的是，长期研究表明，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个临床前动物研究表明，MSC在用于治疗炎症状况时确实具有保护作用。在几种有益效果中，它们的给药始终与炎症大幅减少有关，但是这种现象的机制仍不清楚，并且与免疫细胞相互作用的数据仍然不足和有争议。为了将MSC转化为临床实践，我们必须对其作用机理有更精确的了解。在这项研究中，我们正在寻求建立MSC对真正生理炎症环境的反应。我们已经建立了被正在进行的临床试验的患者刺激的原代人细胞的体外模型，作为炎症微环境的生理学最相关的模仿。我们对那些包含调节分子的囊泡特别感兴趣，称为miRNA。在确定通过细胞外囊泡向原代人细胞的miRNA转移的重要性之后，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来通过分析已在ARDS中使用我们临床MSC进行临床试验的患者的临床样本来验证我们对MSC治疗功效的发现。预期的原则是建立了一种定义且可靠的机制，该机制是MSC细胞疗法的免疫调节作用，该机构为MSCS和MSCS杂物的进一步试验提供了信息。这些发现还将为细胞制造目的的效力分析提供信息，并为未来的MSC工程提供见解，以提高其治疗功效。这项研究的机械数据将使MSC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)

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

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

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

• 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