Case report: A multiple sclerosis patient with imaging features of glymphatic failure benefitted from CSF flow shunting

The derangement of CSF circulation impacts the functions of the glymphatic-lymphatic system (G-Ls), which regulates solute trafficking and immune surveillance in the CNS. The G-Ls failure leads to the dysregulation of clearance of waste molecules in the brain and to an altered CNS immune response. The imaging features of dilated perivascular spaces imply the impairment of the G-Ls. We report on the case of a patient with primary progressive multiple sclerosis and dilatation of perivascular spaces, who transiently improved after CSF shunt diversions. The underlying mechanisms remain to be determined and at this stage, it is not possible to link CSF diversion to an effect on MS pathology. However, this observation provides the rationale to incentivize research in the largely unknown area of CSF dynamic disturbances on G-Ls failure and ultimately in neurodegeneration

FGF2 and ET1 promote human fetal striatal neuroblasts survival in hypoxic conditions

Fetal striatal transplantation emerged as a new strategy to promote reparative responses in Huntington’s disease (HD) patients1. Mechanisms that support neuroblasts survival and replenishment of damaged cells within the HD brain in hypoxia remain to be elucidated. This study investigated how human fetal striatal neuroblasts (HSP cells) respond to hypoxia, using the hypoxia-mimetic agent cobalt chloride (CoCl2)2. We analyzed CoCl2 effect on hypoxia-related proteins, such as HIF-1α and VEGF, and on a neuroprotective factor, such as Seladin-1. Moreover, we evaluated FGF2 (50 ng/ml) and ET1 (100 nM) proliferative/survival effects in HSP cells in normoxic and hypoxic conditions. These growth factors could be important mediators under pathological conditions for striatal neuroblasts function and response to hypoxia. Dose-response experiments with increasing concentration of CoCl2 (50-750 um) showed an increase of HSP cell proliferation at 24-48h, with maximal effects observed at 400 um, while cell survival was impaired at 72h. Hypoxia increased protein expressions of HIF-1α and VEGF, whereas decreased Seladin-1 levels. FGF2 and ET1 significantly stimulated HSP cells proliferation both in normoxic and hypoxic condition, counteracting the apoptotic CoCl2 effect at 72h. FGF2 and ET1 neuroprotective effect was abolished by the selective inhibition of their receptors (FGFR1, ETA and ETB). In particular, ET1 stimulated HSP cells survival through ETA receptor in normoxic condition and through ETB receptor during hypoxia. Our results support the idea that FGF2 and ET1 promote neurogenesis and survival of HSP cells, through receptor-mediated mechanisms, when grafted into the hypoxic HD brain

Human mesenchymal stem cells labelled with dye-loaded amorphous silica nanoparticles: long-term biosafety, stemness preservation and traceability in the beating heart

Treatment of myocardial infarction with mesenchymal stem cells (MSCs) has proven beneficial effects in both animal and clinical studies. Engineered silica nanoparticles (SiO2-NPs) have been extensively used as contrast agents in regenerative medicine, due to their resistance to degradation and ease of functionalization. However, there are still controversies on their effective biosafety on cellular systems. In this perspective, the aims of the present study are: 1) to deeply investigate the impact of amorphous 50 nm SiO2-NPs on viability and function of human bone marrow-derived MSCs (hMSCs); 2) to optimize a protocol of harmless hMSCs labelling and test its feasibility in a beating heart model. Optimal cell labelling is obtained after 16 h exposure of hMSCs to fluorescent 50 nm SiO2-NPs (50 µg mL(-1)); interestingly, lysosomal activation consequent to NPs storage is not associated to oxidative stress. During prolonged culture hMSCs do not undergo cyto- or genotoxicity, preserve their proliferative potential and their stemness/differentiation properties. Finally, the bright fluorescence emitted by internalized SiO2-NPs allows both clear visualization of hMSCs in normal and infarcted rat hearts and ultrastructural analysis of cell engraftment inside myocardial tissue. Overall, 50 nm SiO2-NPs display elevated compatibility with hMSCs in terms of lack of cyto- and genotoxicity and maintenance of important features of these cells. The demonstrated biosafety, combined with proper cell labelling and visualization in histological sections, make these SiO2-NPs optimal candidates for the purpose of stem cell tracking inside heart tissue