The nervous system is a frequent target for the adverse effects of environmental chemicals, including industrial compounds and drugs, and many of these chemicals have been shown to induce neuroinflammation. Evidence is accumulating that neuroinflammation, characterised by the reactivity of both astrocytes and microglial cells, is involved in the pathogenesis of neurodegenerative diseases. Metabolic adaptations have been shown in reactive astrocytes and microglial cells. Furthermore, astrocytic metabolic and inflammatory changes have been recently reported as a function of age, leading to the hypothesis that mitochondrial metabolism and inflammatory responses are interconnected and promote the functional switch of astrocytes, from neurotrophic to neurotoxic.
Our laboratory focuses on two major goals:
- The study of the inflammatory processes triggered by neurotoxic compounds and leading to neurodegeneration.
- The identification of reliable toxicity biomarkers and fundamental cellular pathways targeted by neurotoxins, focusing in particular on metabolic changes occurring during neuroinflammatory processes.
For this purpose, we developed a rat three-dimensionnal cell culture system containing all brain cell types and we are currently developing similar human models starting from human embryonic stem cells (hESC) or human induced pluripotent stem cells (hiPSC).
Development of 3D cell culture systems for drug safety testing and environmental neurotoxins detection.
Toxicity testing has traditionally relied on studies of adverse health effects observed in animals at high doses, with subsequent extrapolations to determine tolerable levels in humans. However, it became recently clear that in vitro studies using mechanistic approaches would be more efficient and more reliable. Our current research work aims at improving the detection of adverse effects in the brain induced by environmental chemicals and drugs in development, by the elucidation of critical pathways affected by these agents. For this purpose, we developed and use the rat aggregating brain cell culture system as a model. This three-dimensional (3D) cell culture system contains all the different brain cell types and allows the multiple cell-cell interactions involved in physiological and pathogenic pathways. After exposure of the cells to environmental compounds or drugs, we measure the perturbation of cell type-specific structural and functional traits (e.g., changes in synaptic, cytoskeletal and myelin components; changes in energy metabolism), and the activation of homeostatic defence mechanisms (e.g., changes in the expression of heat shock proteins; oxidative stress responses; inflammatory responses; apoptosis) using several analytical approaches including global transcriptogenomics, proteomics and metabolomics analyses. This strategy proved to be highly reliable in several large-scale European projects (ACuteTox, Peridct-IV). We are now developing 3D cell culture models starting with human embryonic and human induced pluripotent stem cells (StemBANCC). We also incorporate hiPSCs in 3D rat brain cell cultures in order to take advantage of the histotypic niche created by the rat cells.
Metabolic perturbations of astrocytes during astrogliosis.
Several classes of neurotoxic compounds have been shown to induce neuroinflammation and evidence is accumulating that neuroinflammation, characterised by the reactivity of both astrocytes and microglial cells, is involved in the pathogenesis of neurodegenerative diseases. The role of astrocytes in this process has been less characterised than the role of microglial cells. Metabolic adaptations have been shown in reactive astrocytes and microglial cells. The consequences for the neurons of the changes in cellular metabolism of neighbouring astrocytes during the inflammatory processes are not yet well characterized. However, astrocytic metabolic and inflammatory changes have recently been reported as a function of age, leading to the hypothesis that mitochondrial metabolism and inflammatory responses are interconnected and promote the functional switch of astrocytes, from neurotrophic to neurotoxic. The objective of this project is to describe the metabolic reprogramming of astrocytes occurring during the neuroinflammatory process triggered by selected chemicals, and the relationship between these changes in glial cellular metabolism and neurodegeneration.
Marie-Gabrielle Zurich - Group leader
Biologist with a PhD in neurosciences, Marie-Gabrielle Zurich is a senior scientist and lecturer at the University of Lausanne and for the Swiss Center for Applied Human Toxicology. She has a long experience in in vitro neurotoxicology. Her work focuses both on the search for biomarkers of neurotoxicity and on metabolic changes occurring during glial reactivity.
Denise Tavel – Part-time technician
|Denise Tavel is a well-trained lab technician, having a great expertise in cell cultures, in enzymatic activity analyses, real-time RT-PCR, immunostaining, immunoblotting and in metabolic profiling using Seahorse technology. She manages the lab and is involved in numerous projects with all group members.|
Carolina Nunes - PhD student
|Carolina obtained her Bachelor degree in Biology (2012) and Master degree in Developmental and Evolutionary Biology (2014) in Faculdade de Ciencias Universidade de Lisboa. She carried out her master thesis in Jacinta Serpa’s lab, where she studied the role of the Vascular Endothelial Growth Factor (VEGF) in the modulation of Acute Myeloide Leukaemia (AML). Thereafter she stayed in Jacinta Serpa’s lab with a grant where, alongside developing her previous project, she studied the effect of covalent modification of histones by carcinogens (glycidamide and BDA).
In 2016 she was a trainee in the start-up Allinky Biopharma (Madrid, Spain) through the program INOV Contacto, where she was involved in the test of novel small molecules (allosteric inhibitors) in cell lines, for cancer and inflammation set-ups.
She started being interested in pluripotent stem cells during her internship in Ispra’s Joint Research Center – European Commission (Italy) where she was involved in several projects related to developmental neurotoxicity. Her main focus was to establish a protocol for quantification of synaptogenesis by means of immunocytochemistry and high content imaging (HCI) in Human Induced Pluripotent Stem Cell
(hiPSC)-derived neuronal cells.
Carolina joined Marie-Gabrielle Zurich’s group in September 2017 as a PhD candidate and is currently working in the differentiation of hiPSCs into brain cells and their applications to neurotoxicity testing.
David Pamies - First assistant
|David Pamies did his PhD and MS at Bioengineering Institute of Miguel Hernandez University. The focus of his PhD research was to elucidate the role of neuropathy target esterase (NTE) in the differentiation process, using mouse embryonic stem cells in order to determine their role as a possible target in mammalian embryonic development toxicity and human NT2 cells and function of NTE in the process of differentiation to form the neuroectoderm. During his PhD he did a period of training at European Commission Joint Research Center (JRC), where he was working in new 3D models to assess developmental neurotoxicity (DNT). After his PhD he did a Postdoc followed by a research-associated position at Johns Hopkins University Center for Alternatives to Animal Testing. During that time, he developed an iPSC-derived 3D human brain microphysiological system in order to study DNT, cancer, virus infection, inflammation and other applications. Currently he is working on new cell culture 3D models to study neuroinflammation, astrocytes toxicity and myelin related diseases.|
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