Exosomes regulate neurogenesis and circuit assembly.

Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in dentate gyrus of P4 mouse brain. We compared the protein cargo and signaling bioactivity of exosomes released by hiPSC-derived neural cultures lacking MECP2, a model of the neurodevelopmental disorder Rett syndrome, with exosomes released by isogenic rescue control neural cultures. Quantitative proteomic analysis indicates that control exosomes contain multiple functional signaling networks known to be important for neuronal circuit development. Treating MECP2-knockdown human primary neural cultures with control exosomes rescues deficits in neuronal proliferation, differentiation, synaptogenesis, and synchronized firing, whereas exosomes from MECP2-deficient hiPSC neural cultures lack this capability. These data indicate that exosomes carry signaling information required to regulate neural circuit development

Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury.

The goal of stem cell therapy for spinal cord injury (SCI) is to restore motor function without exacerbating pain. Induced pluripotent stem cells (iPSC) may be administered by autologous transplantation, avoiding immunologic challenges. Identifying strategies to optimize iPSC-derived neural progenitor cells (hiNPC) for cell transplantation is an important objective. Herein, we report a method that takes advantage of the growth factor-like and anti-inflammatory activities of the fibrinolysis protease, tissue plasminogen activator tPA, without effects on hemostasis. We demonstrate that conditioning hiNPC with enzymatically-inactive tissue-type plasminogen activator (EI-tPA), prior to grafting into a T3 lesion site in a clinically relevant severe SCI model, significantly improves motor outcomes. EI-tPA-primed hiNPC grafted into lesion sites survived, differentiated, acquired markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion. Importantly, only SCI rats that received EI-tPA primed hiNPC demonstrated significantly improved motor function, without exacerbating pain. When hiNPC were treated with EI-tPA in culture, NMDA-R-dependent cell signaling was initiated, expression of genes associated with stemness (Nestin, Sox2) was regulated, and thrombin-induced cell death was prevented. EI-tPA emerges as a novel agent capable of improving the efficacy of stem cell therapy in SCI

Blocking Zika virus vertical transmission.

The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity

Author Correction: Blocking Zika virus vertical transmission.

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Expression and function of system xc- and microglial glutamate in ALS models

La SLA est la maladie du motoneurone la plus fréquente chez l adulte conduisant à une paralysie progressive et la mort des patients. Les cellules microgliales, macrophage du SNC, sont impliquées dans la progression de la maladie. Sachant que la SLA est à caractère majoritairement sporadique, cibler la phase symptomatique et donc la microglie, semble pertinent pour la SLA. Les voies spécifiques impliquant la microglie et entraînant la dégénérescence des motoneurones sont encore largement inconnues. Nous avions donc pour objectif d'identifier les facteurs microgliaux agissant au cours de la dégénérescence des motoneurones. Etant donnée l'importance de l'excitotoxicité comme mécanisme potentiellement impliqué dans la neurodégénérescence de la SLA, ce projet a mis l'accent sur le glutamate libéré par les cellules microgliales par le biais du système xc- (sous-unité spécifique: xCT), un antiport cystine / glutamate, exprimé par la microglie. Nos résultats ont montré que les cellules microgliales exprimaient xCT et à un niveau plus élevé lorsqu elles étaient activées. L'ARNm de xCT était également présent dans la moelle épinière de souris et son expression augmentée au cours de la maladie dans la moelle épinière de souris SLA. La délétion de xCT chez les souris SLA a entrainé une accélération du début de la maladie mais a permis de prolonger la durée de la phase symptomatique. Le système xc- microglial était responsable de la libération de glutamate et éliminer xCT a permis de renforcer le phénotype neurotrophique de la microglie. Ces résultats montrent que le système xc- pourrait être une cible pour ralentir la progression de la SLAAmyotrophic lateral sclerosis (ALS) is the most common adult onset motor neuron disease leading to paralysis and death of patients. Mutations in SOD1 are responsible for motor neuron degeneration through a non-cell autonomous mechanism. Microglial cells, the macrophages of the central nervous system, participate in the progression of the disease. Since ALS is mainly sporadic, targeting the symptomatic phase during which microglial cells are actively involved is relevant to ALS. Since microglial neurotoxic factors are still largely unidentified in ALS and excitotoxicity is one pathway suggested to cause motor neuron death, our hypothesis was to assess if glutamate released by microglia through system xc- (a cystine/glutamate antiporter with the specific subunit xCT) could participate to motor neuron death in ALS. We now show that primary microglial cells expressed xCT and to a higher level upon activation, that xCT transcripts were enriched in microglia compared to the whole spinal cord and absent in motor neurons. In addition, xCT mRNA levels were increased in mutant SOD1 mouse spinal cords during disease progression. Deleting xCT in mutant SOD1 mice accelerated the onset of the disease but increased the duration of the symptomatic phase. Microglial system xc- was responsible for release of glutamate by microglial cells and deleting xCT increased the neurotrophic profile of microglial cells. These results show that system xc- could be a good target to slow ALS disease progressionPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Hand functions in type 1 and type 2 diabetes mellitus

Introduction/Objective. Hand functions have an enormous impact on activities of daily living in patients with diabetes mellitus (DM), such as self-care, administering insulin injections, and preparing and eating meals. The aim of the study was to evaluate hand functions and grip strength in patients with type 1 and type 2 DM. Methods. This was an observational case-control study investigating the hand functions and grip strength in patients with type 1 and type 2 DM. The study comprised 41 patients with type 1 DM aged 25–50 years sex- and age-matched, 40 non-diabetic controls, and 91 patients with type 2 DM aged 40–65 years sex- and age-matched 60 non-diabetic controls. Patients with documented history of diabetic sensorimotor neuropathy and adhesive capsulitis were excluded. The Duruoz Hand Index was used to assess the functional hand disability. Grip strength was tested with a calibrated Jamar dynamometer. Results. The Duruoz Hand Index scores in patients with type 2 DM were significantly higher than in persons in the control group (p 0.05). Grip strength values of patients with type 1 DM were significantly lower compared to those in the control group (p < 0.05), whereas there was no significant difference between patients with type 2 DM and their control group. There was a negatively significant correlation between grip strength and the Duruoz Hand Index scores in patients with both type 1 and type 2 DM (p < 0.05). Conclusion. Patients with type 1 DM and type 2 DM have different degrees of hand disability as compared to healthy control groups