**4. Mechanisms by which MSCs exert their effects**

MSCs work by multiple mechanisms and can exert their effect through cell-cell contact, secreting several factors directly to the media or through the release of extracellular vesicles.

It seems that during sepsis and ARDS the MSC are not really engrafted in any tissue; however, it has been demonstrated that cells migrate to the site of the injury and they are retained there for a while. It has been shown that some effects are produced through cell-cell contact between MSCs and alveolar epithelial cells mainly to regulate endothelial integrity creating some junctions and transferring mitochondria or other cellular products with therapeutic effect [58, 60, 89].

In the last sections, we reviewed the effects of MSCs through the secretion of several factors such as antimicrobial peptides, antiapoptotic effectors, or immunomodulatory mediators.

Besides, MSCs release extracellular vesicles, which encapsulate several cellular components, including mitochondria and gene products such as miRNAs and mRNAs. Moreover, it has been described that some extracellular vesicles can also encapsulate lipids and proteins. Several studies have described the delivery of miR-223 that is transfer to macrophages and cardiomyocytes and reduces their inflammatory response. Also, the mRNA from KGF has also been detected inside these extracellular vesicles, producing its effect in the endothelium and epithelium and enhancing their repair [97–99].
