Multiple sclerosis is a neurological disease characterized by chronic inflammation and lesions to myelin, a specialized membrane which enwraps axons, allowing fast nerve impulse transmission. It is widely accepted that microglia, the immune cells of the nervous system, contribute to inflammatory brain damage by directly affecting oligodendrocytes, the myelin forming cells. However, a recent study published in the high impact journal Acta Neuropathologica, coordinated by dr. Claudia Verderio of the CNR Institute of Neuroscience and involving, among other institutions, the University of Milan, (labs of prof. Maria Pia Abbracchio and prof. Paola Viani), the Neuroscience Institute Cavalieri Ottolenghi – University of Turin (prof. Annalisa Buffo’ lab) and the University and the San Martino Hospital in Genoa (prof. Antonio Uccelli’s lab) shows that microglia is always beneficial towards oligodendrocytes but become detrimental through the activation of astrocytes, the most abundant glial cell type in the brain. The work has been supported by a Multiple Sclerosis Innovation Grant of Merk Serono and by Fondazione Italiana Sclerosi Multipla.
“It is widely accepted that microglia can acquire either pro-regenerative or detrimental functions depending on the signals coming from the brain environment. Opposite activation states of microglia can be reproduced in vitro by the use of distinct polarizing agents. Our initial data showed that the action of microglia is mediated by the release of small membrane vesicles in the extracellular space, which are always protective towards oligodendrocytes, independently of the polarizing stimulus used to activate microglia” say Marta Fumagalli and Claudia Verderio (già detto sopra, toglierei da qui). “However,” add Marta Lombardi and Roberta Parolisi “when vesicles produced by microglia exposed in vitro to inflammatory stimuli were injected into the brain, in proximity of the myelin lesion, we observed a clear block in the capacity of the tissue to repair the myelin lesion, suggesting the involvement of other cell types. When we repeated the in vitro experiment in the presence of astrocytes, we found that vesicles derived from inflammatory microglia, which carry the cytokine TNF-alpha, induce a harmful astrocyte transformation that blocks oligodendrocyte differentiation, mimicking the block observed in vivo”.
The latter experiment also showed that mesenchymal stem cells, immunomodulatory cells under clinical evaluation for the treatment of patients affected by multiple sclerosis, decrease TNF-alpha content in microglia and EVs thereof, counteracting the detrimental action of the vesicles mediated by astrocytes. Specifically, it has been demonstrated that mesenchymal stem cells “unmask” the beneficial action of the lipid components of the microglial vesicles, which promote both oligodendrocyte recruitment to the lesion site and differentiation to myelin-forming cells.
“Our study shifts the focus of the scientific community from microglial cells to astrocytes, as primary cellular targets of novel pro-myelinating strategies”. “In addition”, concludes Claudia Verderio, “identification of the vesicle lipids that promote oligodendrocyte maturation will be a fundamental step in the development of new therapies”.
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