Characteristics of extracellular vesicles and their potential role in organ-cross talk after multiple trauma

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The communication of different body compartments through which tissue can affect also distant tissues has gained increasing interest. Due to several observations, this process termed “organ cross-talk” also seems to be of major relevance after multiple trauma (MT). First, the systemic effects of injuries to different body compartments have been shown to be far greater than the sum of the isolated traumatic insults. Second, various posttraumatic dysfunctions of primarily unaffected organs have been described. These observations can contribute to the development of multiple organ dysfunction syndrome (MODS), which is still one of the most common complications in MT patients who survive the initial insult. The posttraumatic immune response is well known to play a key role in both, the interaction of diverse body compartments and the development of organ dysfunction after MT. As injuries of different body regions are associated with distinct local inflammatory responses, which can accumulate in a potentially harmful systemic inflammatory reaction, there is first evidence that also extracellular vesicles (EV), generated from a variety of cells (e.g. organ specific macrophages, endothelial cells and osteoblasts), might be involved in the aforementioned processes. EV-based crosstalk represents a substantial cell-cell communication pattern that exerts its effects either via molecular surfaces or by the transfer of molecules (e.g. proteins, mitochondrial DNA, mRNA) into other cells. These interactions can result in a synchronization of functions among similar cells or a coordination of different cell types. Despite the potential relevance of EV for posttraumatic organ cross-talk, it is unknown if their origin and release pattern is dependent on both, the severity and distribution of the sustained injury. In this context, organ-specific EV might be released either only in case of a direct injury to the organ itself or also due to “indirect” traumatic impacts, such as systemic insults (trauma hemorrhage (TH)) or injuries to other body compartments. Furthermore, detailed characterization of EV in regard to subset composition, their content and function has not been performed. With this project we therefore plan to: a) investigate the injury pattern-dependent local and systemic release of EV in a well-established MT model in pigs. After isolating these local and systemic EV, also characterization of their origin and content will be performed, b) stimulate organ-specific cell lines in vitro with isolated EV from the porcine MT model to illuminate EV-function on cell function and c) translationally compare the systemic release pattern of EV from the large animal model to the human situation (NTF Biobank) and correlate these findings to the development of clinical complications and patients’ outcome.