Mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for ARDS.

间充质干细胞衍生的细胞外囊泡作为 ARDS 的无细胞疗法。

• 批准号: MR/R025096/1
• 负责人: Anna Krasnodembskaya
• 金额: $ 32.1万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR025096%2F1
• 关键词: Mesenchymal; stem; cell; derived; extracellular

Acute Respiratory Distress Syndrome (ARDS) is a severe clinical syndrom that affects 20% of all critically ill patients in intensive care. Unfortunately, around 30-50% of these people will die from the condition and the quality of life of the survivers can be seriously reduced due to the consequent chronic lung problems.There is no effective treatments for this condition at this time and therefore new medicines are urgently needed. ARDS is characterised by an excessive and disregulated inflammation in the lung that leads to inappropriate infiltration of immune cells, lungs fill with water and fail to maintain its main function - breathing. In order to breath these patients require mechanical ventilation.Recently more and more clinicians and basic scientists attention is drawn to cell-based therapies. 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 produce multiple mediators with immuno-modulatory properties. However, concerns regarding safety of long-term effects of MSC administration (e.g. development of tumors) as well as logistical challenges may limit their successful clinical translation. Accumulating evidence now suggests that MSCs act primarily through secretion of different biologically active mediators. Therefore researchers are increasingly considering MSC cell products (which can not replicate and therefore form tumors) as an alternative to the whole cell therapy.In this project we will investigate the therapeutic potential of small membrane wrapped "exracellular vesicles" released by MSCs. These vesicles represent the key component of MSCs secretome and are relatively easy to isolate from MSC conditioned medium by high speed centrifugation. Previously we and others had demonstrated that these vesicles were capable to recapitulate therapeutic effects of MSCs in various pre-clinical models of ARDS. Furthemore, in our recent work we had found that these vesicles contain organelles responsible for maintaining cell bioenergetics (mitochondria). This is very exciting finding as it is known that mitochondrial function is impaired in acute inflammatory conditions such as ARDS.In this project we will use small animal model of ARDS to investigate the therapeutic potential of these vesicles, optimise best route and strategy of administration, gain isights into their bio-distribution in the tissues and also investigate whether or not functionally active mitochondria are important for the therapeutic effect and which tissues are major recipients of the mitochondria transferred in the EVs. These studies will be further complemented by the investigation of the EV mitochndrial transfer to primary human lung cells in vitro. These data are an essential requirement by regulatory bodies such as UK Medicines and Healthcare Products Regulatory Agency and European Medicines Agency for clincal translation of new therapies. The principle anticipated output of this project will be the establishment of a defined strategy for clinical development and knowledge of the specific mechanism of action (based on mitochondrial transfer) of the MSC derived extracellular vesicles. More immediately these data will inform further pre-clinical studies in larger animal models of ARDS required to obtain neccessary data on safety, efficacy and mechanism of action of MSCs EVs. Collectively data in small and large animal models will inform early phase clinical trials for MSC extracellular vesicles in patients with ARDS.

急性呼吸窘迫综合征（ARDS）是一种严重的临床综合征，影响20%的重症监护患者。不幸的是，这些人中大约有30-50%会死于这种疾病，并且由于随之而来的慢性肺部问题，生存者的生活质量会严重降低。目前还没有有效的治疗方法，因此迫切需要新的药物。ARDS的特征是肺部过度和失调的炎症，导致免疫细胞的不适当浸润，肺部充满水，无法维持其主要功能-呼吸。近年来，越来越多的临床医生和基础科学家开始关注基于细胞的治疗。间充质干细胞（MSC）是一种基于细胞的治疗最有前途的候选细胞之一，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。MSC可以在实验室条件下容易地繁殖和操作，并且具有产生具有免疫调节特性的多种介质的能力。然而，对MSC施用的长期作用的安全性（例如肿瘤的发展）以及后勤挑战的担忧可能限制其成功的临床转化。越来越多的证据表明，MSC主要通过分泌不同的生物活性介质发挥作用。因此，越来越多的研究者考虑将MSC细胞产物（不能复制，因此形成肿瘤）作为全细胞治疗的替代方案。在本项目中，我们将研究MSC释放的小膜包裹的“细胞外囊泡”的治疗潜力。这些囊泡代表了MSC分泌组的关键组分，并且通过高速离心相对容易地从MSC条件培养基中分离。以前，我们和其他人已经证明，这些囊泡能够概括MSC在各种临床前ARDS模型中的治疗效果。此外，在我们最近的工作中，我们发现这些囊泡含有负责维持细胞生物能量的细胞器（线粒体）。这是一个非常令人兴奋的发现，因为众所周知，在急性炎症条件下，如ARDS，线粒体功能受损。在这个项目中，我们将使用小动物模型的ARDS研究这些囊泡的治疗潜力，优化最佳途径和给药策略，获得他们的生物-分布在组织中，并研究功能活性线粒体是否对治疗效果重要以及哪些组织是主要受体线粒体在EV中的转移。这些研究将进一步补充EV线粒体转移到原代人肺细胞在体外的调查。这些数据是监管机构（如英国药品和保健产品监管局和欧洲药品管理局）对新疗法临床转化的基本要求。本项目的主要预期产出将是为MSC衍生细胞外囊泡的临床开发和特定作用机制（基于线粒体转移）的知识建立明确的策略。更直接地，这些数据将为在更大的ARDS动物模型中进行的进一步临床前研究提供信息，以获得关于MSC EV的安全性、有效性和作用机制的必要数据。在小型和大型动物模型中的集体数据将为ARDS患者中MSC细胞外囊泡的早期临床试验提供信息。

项目成果

MSC extracellular vesicles ameliorate ARDS via activation of mitochondrial biogenesis

MSC 细胞外囊泡通过激活线粒体生物发生改善 ARDS

• DOI: 10.1183/13993003.congress-2022.3450
• 发表时间: 2022
• 作者: McClintock C

In reply.

回复。

• DOI: 10.3949/ccjm.81c.12002
• 发表时间: 2014
• 期刊: Cleveland Clinic journal of medicine
• 影响因子: 6.1
• 作者: ChingSun,GraceE;Kashyap,SangeetaR;Nasr,Christian
• 通讯作者: Nasr,Christian

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

Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS.

• DOI: 10.1183/13993003.02978-2020
• 发表时间: 2021-07
• 期刊: The European respiratory journal
• 作者: Dutra Silva J;Su Y;Calfee CS;Delucchi KL;Weiss D;McAuley DF;O'Kane C;Krasnodembskaya AD
• 通讯作者: Krasnodembskaya AD

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial.

• DOI: 10.1016/j.eclinm.2021.101167
• 发表时间: 2021-11
• 期刊: EClinicalMedicine
• 影响因子: 15.1
• 作者: Gorman E;Shankar-Hari M;Hopkins P;Tunnicliffe WS;Perkins GD;Silversides J;McGuigan P;Krasnodembskaya A;Jackson C;Boyle R;McFerran J;McDowell C;Campbell C;McFarland M;Smythe J;Thompson J;Williams B;Curley G;Laffey JG;Clarke M;McAuley DF;O'Kane CM
• 通讯作者: O'Kane CM