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，影响重症监护病患者的20％。不幸的是，由于随之而来的慢性肺部问题，这些人中约有30-50％的人会死于状况，幸存者的生活质量可以大大降低。目前对这种情况没有有效的治疗方法，因此紧急需要新药物。 ARDS的特征是肺部过度且无调炎症，导致免疫细胞的不适当浸润，肺充满水，无法维持其主要功能 - 呼吸。为了呼吸这些患者，需要机械通气。越来越多的临床医生和基础科学家注意基于细胞的疗法。基于细胞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，它代表一种成年干细胞（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，没有道德问题。 MSC可以很容易地在实验室条件下传播和操纵，并具有产生具有免疫调节特性的多个介体的能力。但是，对MSC给药长期影响的安全性（例如肿瘤的发展）以及后勤挑战的担忧可能会限制其成功的临床翻译。现在积累的证据表明，MSC主要通过分泌不同的生物活性介体的分泌作用。因此，研究人员越来越考虑MSC细胞产物（无法复制并因此形成肿瘤）作为整个细胞疗法的替代方案。在该项目中，我们将研究MSC释放的小膜包裹的“繁殖囊泡”的小膜的治疗潜力。这些囊泡代表了MSC分泌组的关键成分，并且相对容易通过高速离心与MSC调节培养基分离。以前，我们和其他人已经证明，这些囊泡能够在各种临床前ARDS模型中概括MSC的治疗作用。此外，在最近的工作中，我们发现这些囊泡包含负责维持细胞生物能力（线粒体）的细胞器。 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线粒体转移到电动汽车中。这些研究将进一步补充，并在体外研究了线性的线虫转移到原代人肺细胞。这些数据是监管机构的必不可少的要求，例如英国药品和医疗保健产品监管机构和欧洲药品机构，用于新疗法的细胞翻译。预期该项目的原则将是建立MSC衍生的细胞外囊泡的临床发展和知识的定义策略（基于线粒体转移）。这些数据会立即为获得有关MSCS EV的安全性，有效性和作用机理所需的大型ARD的大型动物模型提供进一步的临床前研究。大小动物模型中的集体数据将为ARDS患者的MSC细胞外囊泡提供早期临床试验。

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

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

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