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Synthetic nanoparticles as an innovative treatment for sepsis (SPRINT-4-SEPSIS)

19th national competition for scientific and technical research

Sepsis: Early Warning, Prevention and Treatment

Senior Researcher : Antonio Artigas Raventós

Abstract

 Sepsis is a complex syndrome produced by a systemic infection that is accompanied by a dysregulated host immune response, causing, in many cases, an acute respiratory distress syndrome (ARDS) associated with a mortality rate of 40%. Despite decades of research, there is still a lack of a specific treatment. It is well established that the administration of mesenchymal stromal cells (MSC) has a remarkable therapeutic effectiveness and that its paracrine activity, mediated by the secretion of exosomes, has a crucial role on MSCs’ action.
In our approximation, we aim at devising a free-cell therapeutic strategy based on the production of synthetic nanovesicles carrying specific proteins and miRNAs from MSC-derived exosomes cargo that will down-regulate inflammation, will assist the restoration of systemic immune homeostasis and improve the lung injury in a sepsis model.
During the second year of the project we have demonstrated that pre-stimulating MSC with LPS (mimicking a septic environment) enhances their paracrine activity by increasing the amount of secreted exosomes. In addition, through a scrach assay, we observed that the treatment of epithelial cells with exosomes derived from pre-stimulated MSC (LPS exosomes) increases a 10% its capacity to proliferate and to regenerate the wound healing in comparison with the epithelial cells treated with exosomes derived from non pre-stimulated MSC. We also observed that both LPS and control exosomes were able to decrease the expression of pro-inflammatory cytokines by pre-activated macrophages at the same level. This results were confirmed by an analysis of the protein content of both types of exosomes. This revealed that pre-conditioning MSCs to a septic environment modifies the protein cargo of its exosomes, resulting in the appearance proteins related to cell cycle regulation, cell proliferation and proteins with a key role on suppressing hyperinflammation.
We have rised a promising first step towards a cell-free therapeutic strategy for sepsis, demonstrating the potential regenerative and anti-inflamatory effect of MSC-derived exosomes and by studying the specific components in charge of this therapeutic activity. 

 

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