Abstract
Cell based-therapies represent promising strategies for the treatment of neurological diseases. We have previously shown that adipose stem cells (ASC) ameliorate chronic experimental autoimmune encephalomyelitis (EAE). Recent evidence indicates that most ASC paracrine effects are mediated by extracellular vesicles, i.e. micro- and nanovesicles (MVs and NVs). We show that preventive intravenous administration of NVs isolated from ASC (ASC-NVs) before disease onset significantly reduces the severity of EAE and decreases spinal cord inflammation and demyelination, whereas therapeutic treatment with ASC-NVs does not ameliorate established EAE. This treatment marginally inhibits antigen-specific T cell activation, while reducing microglial activation and demyelination in the spinal cord. Importantly, ASC-NVs inhibited integrin-dependent adhesion of encephalitogenic T cells in vitro, with no effect on adhesion molecule expression. In addition, intravital microscopy showed that encephalitogenic T cells treated with ASC NVs display a significantly reduced rolling and firm adhesion in inflamed spinal cord vessels compared to untreated cells. Our results show that ASC-NVs ameliorate EAE pathogenesis mainly by inhibiting T cell extravasation in the inflamed CNS, suggesting that NVs may represent a novel therapeutic approach in neuro-inflammatory diseases, enabling the safe administration of ASC effector factors.
Highlights
Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are immune-mediated disorders of the central nervous system (CNS), characterized by inflammation, demyelination and axonal degeneration[1,2]
These results demonstrate that adipose stem cells (ASC)-NVs prevent chronic EAE development by limiting immune cell infiltration and CNS inflammation, whereas had no effect once inflammatory cells have already entered the CNS
It has been recently shown that the administration of conditioned medium from mesenchymal stem cells (MSC) may mimic the beneficial effects of MSC administration, indicating that MSC engraftment is not ASC-NVs
Summary
Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are immune-mediated disorders of the central nervous system (CNS), characterized by inflammation, demyelination and axonal degeneration[1,2]. A growing body of literature indicates that ASC exert their action by producing soluble factors, which modify the microenvironment resulting in neuroprotective and immuno-modulating effects[17,18,19], and this paracrine effect provide the basis for an attractive non-cell-based therapy for autoimmune disorders Among these factors, two types of extracellular vesicles have been recently studied: nanovesicles (NVs) and the larger microvesicles (0.1–1 μm)[20,21]. We show that the preventive administration of NVs isolated from ASC (ASC-NVs) ameliorates chronic EAE by inhibiting T cell adhesion in inflamed CNS venules and trafficking to the CNS in EAE mice, leading to reduced spinal cord inflammation, microglial activation and demyelination From their parental cells, ASC-NVs had no effect when administered at disease onset and displayed limited effect on T cell activation and cytokine production. Our data suggest that ASC-NVs may represent a novel therapeutic approach for neurological autoimmune diseases, including MS
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