DNF Seminar series
Abstract: The vesicle behind the fusion behind the transdifferentation - functional RNA transfer from blood to brain by extracellular vesicles.
Mechanisms how the immune system signals to the brain in response to systemic inflammation are not fully understood. We studied the interaction of these tissues in the context of cell fusion, an issue that has been discussed controversially in the recent past. We asked whether cell fusion between blood cells and neurons occurs without highly invasive experimental conditions such as lethal irradiation or chemoablation. For the endogenous irreversible labelling of blood cells we used a transgenic mouse expressing Cre-recombinase under the vav1 promoter specifically in the hematopoietic lineage in a Cre reporter background. Using this model, we observed recombination in non-hematopoietic tissues, including the brain, in the absence of cell fusion. We eventually established that blood cells release extracellular vesicles, including exosomes, containing Cre recombinase mRNA but not protein. Transfer of Cre mRNA by EVs therefore leads to the production of functional Cre protein and subsequent initiation of marker gene expression. Neurons that received functional RNA via extracellular vesicles displayed a distinct miRNA profile compared to their non-recombined counterparts indicating changes the possibility of a regulation of gene-expression. So far communication between blood and nerve cells was understood mainly as being based on individual proteins, such as cytokines. We now identified a novel type of intercellular communication based on the direct transfer of functional RNA, contained in extracellular vesicles that is particularly activated after systemic inflammations. This is also the first demonstration that functional extracellular vesicle-mediated transfer of RNA between tissues occurs in vivo.