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

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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.