Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSCs induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSCs (ASCs) before disease onset significantly reduces the severity of EAE by immune modulation and decreases spinal cord inflammation and demyelination. ASCs preferentially home into lymphoid organs but also migrates inside the central nervous system (CNS). Most importantly, administration of ASCs in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASCs expresses activated a4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging shows that a4 integrins control ASC accumulation in inflamed CNS. Importantly, we found that ASC cultures produce basic fibroblast growth factor, brain-derived growth factor, and platelet-derived growth factor-AB. Moreover, ASC infiltration within demyelinated areas is accompanied by increased number of endogenous oligodendrocyte progenitors. In conclusion, we show that ASCs have clear therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuroregeneration by endogenous progenitors in animals with established disease. Overall, our data suggest that ASCs represent a valuable tool for stem cell-based therapy in chronic inflammatory diseases of the CNS. STEM CELLS
Adult mesenchymal stem cells derived from adipose tissue (A-MSC) have the capacity to differentiate in vitro into mesenchymal as well as endodermal and ectodermal cell lineages. We investigated the neuronal differentiation potential of human A-MSC with a protocol which included sphere formation and sequential culture in brain-derived neurotrophic factor (BDNF) and retinoic acid (RA). After 30 days, about 57% A-MSC showed morphological, immunocytochemical and electrophysiological evidence of initial neuronal differentiation. In fact, A-MSC displayed elongated shape with protrusion of two or three cellular processes, selectively expressed nestin and neuronal molecules (including GABA receptor and tyroxine hydroxilase) in the absence of glial phenotypic markers. Differentiated cells showed negative membrane potential (-60 mV), delayed rectifier potassium currents and TTX-sensitive sodium currents. Such changes were stable for at least 7 days after removal of differentiation medium. In view of these results and the easy availability of adipose tissue, A-MSC may be a ready source of adult MSC with neuronal differentiation potential, an useful tool to treat neurodegenerative diseases.
Purpose: Sodium fluorescein is a dye that, intravenously injected, selectively accumulates in high-grade glioma (HGG) tissue through a damaged blood-brain barrier. In this article, the final results of a multicentric prospective phase II trial (FLUO-GLIO) on fluorescein-guided HGG resection through a dedicated filter on the surgical microscope were reported.Methods: Patients with suspected HGGs considered suitable for removal were eligible to participate in this trial. Fluorescein was intravenously injected at a dose of 5 to 10 mg/kg. The primary endpoint was the percentage of patients with histologically confirmed HGGs, without contrast-enhancing tumor at the immediate postoperative MRI. Secondary endpoints were PFS, residual tumor on postoperative MRI, overall survival, neurologic deficits, and fluorescein-related toxicity. The sensitivity and specificity of fluorescein in identifying tumor tissue were estimated by fluorescent and nonfluorescent biopsies at the tumor margin. The study was registered on the European Regulatory Authorities website (EudraCT 2011-002527-18).Results: Fifty-seven patients aged 45 to 75 years were screened for participation, and 46 were considered for primary and secondary endpoints. Mean preoperative tumor volume was 28.75 cm 3 (range, 1.3-87.8 cm 3 ). Thirty-eight patients (82.6%) underwent a complete tumor removal. Median follow-up was 11 months. PFS-6 and PFS-12 were 56.6% and 15.2%. Median survival was 12 months. No adverse reaction related to SF administration was recorded. The sensitivity and specificity of fluorescein in identifying tumor tissue were respectively 80.8% and 79.1%.Conclusions: Fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and enables a high percentage of contrast-enhancing tumor in patients with HGGs.
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