Anti-inflammatory mesenchymal stromal cell-derived extracellular vesicles improve pathology in Niemann-Pick type C disease

Niemann-Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and lysosomes. The involved disease mechanisms are still incompletely understood, making the design of a rational treatment very difficult. Since the disease is characterized by peripheral inflammation and neuroinflammation and it is shown that extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs) provide immunomodulatory capacities, we tested the potential of MSC-EV preparations to alter NPC1 disease pathology. Here, we show that the administration of an MSC-EV preparation with in vitro and in vivo confirmed immune modulatory capabilities is able to reduce the inflammatory state of peripheral organs and different brain regions of NPC1-diseased mice almost to normal levels. Moreover, a reduction of foamy cells in different peripheral organs was observed upon MSC-EV treatment of NPC1(-/-) mice. Lastly, the treatment was able to decrease microgliosis and astrogliosis, typical features of NPC1 patients that lead to neurodegeneration. Altogether, our results reveal the therapeutic potential of MSC-EVs as treatment for the genetic neurovisceral lipid storage disease NPC, thereby counteracting both central and peripheral features

Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes

Abstract Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the most important ammonia-metabolizing cells in the brain, and microglia, the main immunomodulatory cells in the brain, have been heavily implicated in HE development. As insight into cellular perturbations driving brain pathology remains largely elusive, we aimed to investigate cell-type specific transcriptomic changes in the HE brain. In the recently established mouse bile duct ligation (BDL) model of HE, we performed RNA-Seq of sorted astrocytes and microglia at 14 and 28 days after induction. This revealed a marked transcriptional response in both cell types which was most pronounced in microglia. In both cell types, pathways related to inflammation and hypoxia, mechanisms commonly implicated in HE, were enriched. Additionally, astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction. Accordingly, both monocytes and neutrophils accumulated in the BDL mouse brain. Time-dependent changes were limited in both cell types, suggesting early establishment of a pathological phenotype. While HE is often considered a unique form of encephalopathy, astrocytic and microglial transcriptomes showed significant overlap with previously established gene expression signatures in other neuroinflammatory diseases like septic encephalopathy and stroke, suggesting common pathophysiological mechanisms. Our dataset identifies key molecular mechanisms involved in preclinical HE and provides a valuable resource for development of novel glial-directed therapeutic strategies. Graphical Abstrac

Involvement of the choroid plexus in the pathogenesis of Niemann-Pick disease type C

Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer's, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer's disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1(-/-) mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1(-/-) choroid plexus explants are able to induce typical brain pathology characteristics of NPC1(-/-), more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.</p

Choroid plexus-derived extracellular vesicles exhibit brain targeting characteristics

The brain is protected against invading organisms and other unwanted substances by tightly regulated barriers. However, these central nervous system (CNS) barriers impede the delivery of drugs into the brain via the blood circulation and are therefore considered major hurdles in the treatment of neurological disorders. Consequently, there is a high need for efficient delivery systems that are able to cross these strict barriers. While most research focuses on the blood-brain barrier (BBB), the design of drug delivery platforms that are able to cross the bloodcerebrospinal fluid (CSF) barrier, formed by a single layer of choroid plexus epithelial cells, remains a largely unexplored domain. The discovery that extracellular vesicles (EVs) make up a natural mechanism for information transfer between cells and across cell layers, has stimulated interest in their potential use as drug delivery platform. Here, we report that choroid plexus epithelial cell-derived EVs exhibit the capacity to home to the brain after peripheral administration. Moreover, these vesicles are able to functionally deliver cargo into the brain. Our findings underline the therapeutic potential of choroid plexus-derived EVs as a brain drug delivery vehicle via targeting of the blood-CSF interface

Final report of the regional key comparison EURAMET.M.G-K1: European Comparison of Absolute Gravimeters ECAG-2011

International audienceDuring November 2011 a EURAMET key comparison of absolute gravimeters was organized in the Underground Laboratory for Geodynamics in Walferdange, Luxemburg. The comparison assembled 22 participants coming from 16 countries and four different continents. The comparison was divided into two parts: a key comparison that included six National Metrology Institutes or Designated Institutes, and a pilot study including all participants. The global result given by the pilot study confirms that all instruments are absolutely coherent with each other. The results obtained in the key comparison confirm a good agreement between the NMI instruments. Finally, a link to ICAG-2009 shows also that the NMI gravimeters are stable in time

Final report of the regional key comparison EURAMET.M.G-K1: European Comparison of Absolute Gravimeters ECAG-2011

International audienceDuring November 2011 a EURAMET key comparison of absolute gravimeters was organized in the Underground Laboratory for Geodynamics in Walferdange, Luxemburg. The comparison assembled 22 participants coming from 16 countries and four different continents. The comparison was divided into two parts: a key comparison that included six National Metrology Institutes or Designated Institutes, and a pilot study including all participants. The global result given by the pilot study confirms that all instruments are absolutely coherent with each other. The results obtained in the key comparison confirm a good agreement between the NMI instruments. Finally, a link to ICAG-2009 shows also that the NMI gravimeters are stable in time

The European Comparison of Absolute Gravimeters 2011 (ECAG-2011) in Walferdange, Luxembourg: results and recommendations

We present the results of the third European Comparison of Absolute Gravimeters held in Walferdange, Grand Duchy of Luxembourg, in November 2011. Twenty-two gravimeters from both metrological and non-metrological institutes are compared. For the first time, corrections for the laser beam diffraction and the self-attraction of the gravimeters are implemented. The gravity observations are also corrected for geophysical gravity changes that occurred during the comparison using the observations of a superconducting gravimeter. We show that these corrections improve the degree of equivalence between the gravimeters. We present the results for two different combinations of data. In the first one, we use only the observations from the metrological institutes. In the second solution, we include all the data from both metrological and non-metrological institutes. Those solutions are then compared with the official result of the comparison published previously and based on the observations of the metrological institutes and the gravity differences at the different sites as measured by non-metrological institutes. Overall, the absolute gravity meters agree with one another with a standard deviation of3.1 µ Gal. Finally, the results of this comparison are linked to previous ones. We conclude with some important recommendations for future comparisons