Therapeutic Potential of Extracellular Vesicles for Demyelinating Diseases; Challenges and Opportunities

Multiple Sclerosis is a demyelinating disease of the central nervous system for which no remyelination therapy is available and alternative strategies are being tested. Extracellular vesicles (EVs) have emerged as players in physiological and pathological processes and are being proposed as therapeutic targets and mediators. More concretely, EVs have shown to be involved in myelination related processes such as axon-oligodendrocyte communication or oligodendrocyte precursor cell migration. In addition, EVs have been shown to carry genetic material and small compounds, and to be able to cross the Blood Brain Barrier. This scenario led scientists to test the ability of EVs as myelin regeneration promoters in demyelinating diseases. In this review we will address the use of EVs as remyelination promoters and the challenges and opportunities of this therapy will be discussed

The role of diet related short chain fatty acids in multiple sclerosis

Trabajo presentado en The 35th European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), celebrado en Estocolmo (Suecia), del 11 al 13 de septiembre de 2019[Background] There is growing evidence that gut microbiota is altered in multiple sclerosis (MS). Microbial dysbiosis is characterized by the increase in the genera Methanobrevibacter, Akkermansia, Acinetobacter, Pseudomonas, Blautia and Ruminococcus; and decrease in Sutterella, Faecalibacterium, Prevotella, Fusobacterium, Anaerostipes, Clostridium cluster XIVa and IV, Parabacteroides and Butyricimonas. However, the understanding of how these changes affects the disease development and evolution requires the functional study of the microbiota. Microorganisms produce thousands of biologically active compounds to communicate and interact with their host. Between them could be remarked the short chain fatty acids (SCFAs) as important mediators of the interaction with the neuroendocrine and immune systems. [Aims]: Characterize the profile of fecal SCFAs in MS patients and controls and determine its relation with the fiber intake and the disease. [Methods]: A total of 20 MS patients and 20 controls participated in the study. All participants filled a complete nutritional test and provide a fecal sample. SCFAs were extracted from feces using formic acid (20%v/v) and methanol. 2-Ethylbutyric acid was used as internal control. Analysis was performed using gas chromatography and the acids acetic, propionic, butyric, isobutyric, valeric, isovaleric and caproic were determined. [Results]: The amount of total SCFAs and every single acid evaluated was lower on MS patients regardless the fiber intake. The dominant SCFAs acetic, propionic and butyric were between 20 and 30% lower in MS patients than in controls; major differences were observed on caproic acid (43%). Besides, MS patients showed an altered SCFA profile in comparison with healthy controls, characterized by the higher representation of isobutyric, acetic and isovaleric acids and lower of butyric and caproic acids. Regarding the fiber intake the most affected SCFAs were the acetic and butyric acids. Interestingly the total SCFAs in MS patients seems to diminish with the disease evolution and EDSS score. [Conclusion]: MS patient’s microbiota produces lower levels of SCFAs and presents an altered SCFAs profile. Besides, differences are more pronounced when EDSS score increases and disease progresses. Those results provide valuable information for the evaluation of SCFAs as biomarkers of the disease evolution and the establishment of nutritional patterns directed to the increase of SCFAs producti

MiR-219a-5p enriched extracellular vesicles induce OPC differentiation and EAE improvement more efficiently than liposomes and polymeric nanoparticles

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood–brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression

Stromal Oncostatin M cytokine promotes breast cancer progression by reprogramming the tumour microenvironment

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression