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12:00 – 12:30 Paula Izquierdo

Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation and restore cognitive and motor function in hyperammonemic rats.

Chronic hyperammonemia, a main contributor to hepatic encephalopathy, leads to neuroinflammation which alters neurotransmission leading to cognitive impairment. Currently there are no specific treatments for the neurological alterations in hepatic encephalopathy. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) reduce neuroinflammation in some pathological conditions.
The aim of this work was to assess if treatment of hyperammonemic rats with EVs from MSCs reduces neuroinflammation, improves neurotransmission in hippocampus and cerebellum and restores cognitive and motor function and to study the mechanisms involved.
Treatment of EVs from MSCs was performed in vivo by i.v. injection and ex vivo in hippocampal and cerebellar slices from hyperammonemic or control rats. Hyperammonemia induced neuroinflammation in hippocampus and cerebellum and impaired learning, memory and motor coordination in the tests performed (object location and recognition, Y maze, radial maze and beam walking). Treatment with EVs reduced microglia and astrocytes activation, NF-kB activation and restored performance of hyperammonemic rats in all the behavioral tests. Studies adding EVs to slices ex vivo showed that these beneficial effects were dependent on TGFβ contained in the EVs, which reduced NF-kB activation and the subsequent neuroinflammation.
Conclusions: EVs from MSCs reduce neuroinflammation in hippocampus and cerebellum and restore cognitive and motor function in hyperammonemic rats. EVs from MSCs may be useful to improve cognitive function in patients with MHE.

12:30 – 13:00 Susana Torres

Role of Galectin-3 as an immunosuppressive regulator in 3D models in non-small cell lung cancer (NSCLC). Translational implications.

As the leading cause of cancer death worldwide, lung cancer remains a major burden on healthcare systems and cause significant challenges for clinicians and patients, with ~15% of patients surviving five years after diagnosis. In recent years, there has been an increasing recognition of the immune system’s role in cancer development and progression, focusing on using immunotherapy in the clinic. The role of the immune system during tumorigenesis is crucial. There is a lot of evidence indicating that tumour cells can create an immunosuppressive microenvironment that favours tumour development and spreading. Due to the fact that interactions between tumour cells and immune cells are involved in the down-regulation of the immune response allowing tumour escape from immunosurveillance, a better understanding of how tumour cells interact with their immune microenvironment in NSCLC will result in an improved characterization of patient`s immune contexture (through the use of biomarkers), and new immunotherapeutic protocols which may overcome the limitations of conventional therapeutic strategies. This study explores the role of Galectin-3, an immunoregulatory factor, in the lung cancer microenvironment using tumorspheres (3D models) and evaluates its predictive and prognostic impact in adenocarcinoma (ADC) NSCLC patients. We revealed that Galectin-3 represents a potential factor that modulates the immune microenvironment by regulating Tregs and might be used as a prognostic factor for improved survival in early ADC NSCLC patients and can also be used as a predictive and prognostic factor for improved survival in advanced ADC NSCLC patients treated with first-line pembrolizumab.

Defensa de Tesis Doctoral:

MOLECULAR MECHANISMS BY WHICH CHRONIC HYPERAMMONEMIA INDUCES NEUROINFLAMMATION AND ALTERATIONS IN NEUROTRANSMISSION IN THE CEREBELLUM OF HYPERAMMONEMIC RATS

Doctorando: Yaiza Maria Arenas Ortiz

Directoras:

Resumen:

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that results from liver failure. Liver failure induces hyperammonemia and peripheral inflammation leading to neuroinflammation with activation of microglía and astrocytes and increased levels of pro-inflammatory cytokines. Neuroinflammation alters neurotransmission, leading to cognitive and motor impairment. Rats with chronic hyperammonemia reproduce the cognitive and motor deficits exhibited by patients with minimal hepatic encephalopathy (MHE). In both patients and animal models, the cerebellum appears to be the first area of the brain affected at early stages of MHE. The main objective of this thesis was to identify molecular mechanisms and signal transduction pathways by which chronic hyperammonemia induces neuroinflammation and how this alters neurotransmission in the cerebellum of hyperammonemic rats without liver failure.
In the first chapter, we show that glycinergic neurotransmission modulates neuroinflammation. In hyperammonemic rats, enhanced glycinergic neurotransmission leads to reduced membrane expression of ADAM17, resulting in increased surface expression and activation of TNFR1, of the associated pathway and of NF-κB. This leads to increased expression in Purkinje neurons of TNFα, IL-1b, HMGB1 and glutaminase. This altered neurotransmission leads to motor incoordination. Reducing glycine receptors activation with strychnine or extracellular cGMP normalizes the above pathway in hyperammonemic rats. In the second chapter, we show that sustained (but not short term) hyperammonemia induces TNFα expression in Purkinje neurons, which would be due to TNFR1 activation by TNFα produced in glia which would induce nuclear translocation of NF-κB and TNFα mRNA transcription. Induction of TNFα in Purkinje neurons would alter their function and contribute to altered neurotransmission and neurological impairment. TNFα is also induced in Purkinje neurons of patients died with liver cirrhosis, which would contribute to the loss of Purkinje cells in these patients. In the third chapter, we show that chronic hyperammonemia enhances the activation of S1PR2 by increasing its membrane surface expression. This leads to increased CCL2 levels, especially in Purkinje neurons. CCL2 released by neurons activates CCR2 in microglia, leading to microglia activation and increased membrane expression of P2X4R and content of BDNF, which activates TrkB in Purkinje neurons, leading to increased membrane expression of KCC2. This in turn enhances both GABAergic and glycinergic neurotransmission, which is responsible for motor incoordination in hyperammonemic rats. In conclusion we show that blocking glycine receptor or using R7050 or S1PR2 antagonists have beneficial effects to reduce glial activation and neuroinflammation and improve inhibitory neurotransmission in cerebellum and motor incoordination in chronic hyperammonemia and, likely, in patients with liver cirrhosis and MHE.

12:00 – 12:30 Snezana Dordevic

12:30 – 13:00 Álvaro Ballesteros

12:00 – 12:30 Stefania Carobbio

12:30 – 13:00 Diego Leiva