MacBeth : Macrophage Switch, Esculape : Exosome
Support : SiricOncoLille
Partners : COL, OCR, Univ. Mainz (Dr. A. Vigouroux)
The project deals with the development of a therapeutic strategy allowing macrophages activation within tumor. The immunosuppressive environment created by tumor cells orients macrophages phenotype toward a pro-tumor phenotype. They will then participate to tumor growth by acting directly on tumor cells but also by suppressing T lymphocytes cytotoxic response. They are a key component of tumor environment. The challenge is to find a way to counter this immunosuppression and reactivate macrophages. Our strategy is to use a proproteins convertases inhibitor combined with a TLR receptor ligand to reactivate tumor associated macrophages in glioma. In this context, we have recently demonstrated that macrophages activation could be modulated via an enzyme called proprotein convertase 1/3 (PC1/3). Inhibition of this enzyme triggers an abundant secretion of immune factors and orients macrophages toward a M1 pro-inflammatory phenotype. Activation of these macrophages is even more important when they are stimulated with TLRs ligands.
These macrophages also secret anti-tumor factors effective against glioma cells and also act on their invasion. Then our aim is to develop a therapeutic strategy to reactivate macrophages via PCs inhibitor combined with a TLR receptor ligand. These studies will be led, in a first time in vitro to test the different possible combinations, by using a 3 dimensional cell culture system allowing to mimic tumor complexity. We will then move to an ex vivo tumor explants culture system. Finally, we will finish with ex and in vivo experiment by using explant, and dog patients.
Neurobridge : Combinatory treatment for spinal cord injury using smart biomaterials and gene therapy
Support : PHC Stefanik
Partners : CHRU Lille, Institute of Neuroimmunology SAS (Pr. D. Cizkova), OCR, Ben-Gurion Univ (Pr. S. Cohen), Netherlands Institute Neuroscience (Pr. J. Verhaagen)
Spinal cord injury (SCI) is among the most devastating of traumatic injuries and can result in severe sensory and motor deficits with many serious complications. The primary mechanical damage and axonal disruption in the spinal cord are followed by a cascade of secondary deleterious reactions leading to a spread of the initial lesion and to worsening of the neurological status. Axonal regeneration is repressed by severe inflammation, lack of trophic support and an inhibitory chemical and physical environment. In this context, the self-regeneration and reorganization ability of the central nervous system is insufficient to lead to significant functional recovery and, despite extensive researches; current treatments are still unable to restore lost function in an injured spinal cord. Thus, no effective treatment of SCI exists at present, and it is extremely urgent to find novel and effective therapeutic strategies that could also be translated early into clinical application. To accelerate the translation of tissue-engineered products to human therapies, it is therefore essential to find appropriate scaffold with scalable manufacturing and detailed preclinical testing.
NEUROBRIDGE aims to enable an advanced therapy of spinal cord injury (SCI ) by developing smart biomaterials with multiple functionalities to improve regeneration in patients by controlling the duration and extent of the inflammation after SCI in order to reduce secondary damage, increase tissue sparing, enhance endogenous plasticity and foster tissue repair. Our objectives exploit the principles underlying neurostimulating properties via 1) natural smart "bridges" to stimulate nerve tissue re-building processes at the central lesion cavity including grafted alginate with growth factors and exosomes from Sstem Cells, and 2) treatment with Rho A inhibitor and viral vectors for over-expressing CD16 in neurons to promote neurite outgrowth. The proposed neuron-targeted delivery system is expected to constitute a more advanced concept in the context of SCI regenerative therapies. After in vitro validation, we will conduct a proof of concept first in rats then in a pre-clinical trial on car crashed dogs
Quanico J, Hauberg-Lotte L, Devaux S, Rose M, Meriaux C, Laouby Z, Westerheide L, Raffo Romero A, Vehmeyer J, Rodet F, Maass P, Cizkova D, Zilka N, Blaskao J, Fournier I, Salzet M, Mass Spectrometry Imaging reveals heterogeneous disruption of lipid distribution along the rostro caudal axis in rat spinal cord injury Scientific Report (submitted)
Cizkova D, Cubinkova V, Smolek T, Murgoci AN, Danko J, Vdoviakova K, Humenik F, Cizek M, Quanico J, Fournier I, Salzet M (2018) Localized Intrathecal Delivery of Mesenchymal Stromal Cells Conditioned Medium Improves Functional Recovery in a Rat Model of Spinal Cord Injury Int J Mol Sci. 15;19(3). pii: E870 Download PDF
Devaux S, Cizkova D, Mallah K, Karnoub MA, Laouby Z, Kobeissy F, Blasko J, Nataf S, Pays L, Meriaux C, Fournier I, Salzet M (2017) RhoA Inhibitor Treatment At Acute Phase of Spinal Cord Injury May Induce Neurite Outgrowth and Synaptogenesis Molecular & cellular proteomics : 2017 16, 1394-1415 Download PDF
Devaux S, Cizkova D, Quanico J, Franck J, Nataf S, Pays L, Hauberg-Lotte L, Maass P, Kobarg JH, Kobeissy F, Meriaux C, Wisztorski M, Slovinska L, Blasko J, Cigankova V, Fournier I, Salzet M (2016) Proteomic Analysis of the Spatio-temporal Based Molecular Kinetics of Acute Spinal Cord Injury Identifies a Time and Segment-specific Window for Effective Tissue Repair Molecular & cellular proteomics : 15, 2641-2670 Download PDF
Slovinska L, Szekiova E, Blasko J, Devaux S, Salzet M, Cizkova D (2015) Comparison of dynamic behavior and maturation of neural multipotent cells derived from different spinal cord developmental stages: an in vitro study. Acta neurobiologiae experimentalis 75, 107-114 Download PDF
Cizkova D, Slovinska L, Grulova I, Salzet M, Cikos S, Kryukov O, Cohen S (2015) The influence of sustained dual-factor presentation on the expansion and differentiation of neural progenitors in affinity-binding alginate scaffolds Journal of tissue engineering and regenerative medicine 9, 918-929 Download PDF
Cizkova D, Devaux S, Le Marrec-Croq F, Franck J, Slovinska L, Blasko J, Rosocha J, Spakova T, Lefebvre C, Fournier I, Salzet M (2014) Modulation properties of factors released by bone marrow stromal cells on activated microglia : an in vitro study Scientific reports 4, 7514 Download PDF
Cizkova D, Le Marrec-Croq F, Franck J, Slovinska L, Grulova I, Devaux S, Lefebvre C, Fournier I, Salzet M (2014) Alterations of protein composition along the rostro-caudal axis after spinal cord injury: proteomic, in vitro and in vivo analyses Frontiers in cellular neuroscience 8,105 Download PDF
Book Chapters & Reviews
Cizkova D, Murgoci A, Kresakova L, Vdoviakova K, Smolek T, Cubínková V, Quanico J, Fournier I, Salzet M Understanding molecular pathology along injured spinal cord axis : moving frontiers toward effective neuroprotection and regeneration (2017) Essentials Of Spinal Cord Injury. InTechOPen
Cizkova D, Qunaico J, Karboub MA, Zairi F, Rodet F, Murgoci AN, Cubinlova V, Fournier I, Salzet M (2018) Shedding new light on spinal cord injury via a spatio-temporal proteomic and physiological approaches. Anals of Trauma & Acute Care 2(1)
Nobody : Antibody therapy
Do neural cells produce true antibodies ?
Partners : CHRU Lille, Institute of Neuroimmunology SAS (Pr. D. Cizkova)
Antibodies, also named Immunoglobulins (Ig), are key molecular players in the regulation and mediation of immune responses. A highly complex molecular mechanism that is specific to a sub-population of immune cells, namely B-cell progenitors, supports the diversification of antibody synthesis. This process allows thus the production of a quasi-infinite number of distinct antibodies that can specifically recognize a quasi-infinite number of target antigens. While Ig synthesis is considered as a prerogative of the immune system, recent works demonstrated that cancer cells may produce immunoglobulins type G (IgGs). Moreover, our data on spinal cord injury showed that astrocytes exhibit intracellular IgGs in a frame time that is not compatible with the intra-CNS (central nervous system) generation of IgGs par B-cells. Our hypothesis is that B-cells are not the exclusive source of IgGs
Phenoswitch : Can astrocytes switch in another phenotype ?
Support : Emerging project
We previously showed that macrophages can express an endocrine phenotype and revealed the presence of neuropeptide precursors in macrophages as well as pro-protein convertase hormones implicated in their maturation. We also found the possibility that protein encoded thereby that regulate the secretory pathway and/or the neuroendocrine phenotype (NEP) in cells. We try to find if Master genes can be involved in modulation of the formation of the regulated secretory pathway. One gene found is related to Zis-SR a novel sequence involved in the secretory pathway in cells. Another one is related to a Ghost protein involved in neuronal phenotype expression in astrocytes. The project is thus to identify the partner and the complete function of this Ghost protein in astrocytes.
Exodus : Microglia Extracellular vesicules as cross-talk messenger with astrocytes and neurons
Support : ANR
Partners : CHRU Lille, Institute of Neuroimmunology SAS (Pr. D. Cizkova)
Microglia exert a major role in the repair and Regenesis process and the understanding of the communications between microglia and other glia cells and neurons is one major fundamental event needs to be depict for finding the best time windows for the therapeutic actions. In this purpose Extracellular vehicles (EVs) released by all cells of the nervous system not only during development and homeostasis but also under pathological conditions are one elements that need to be taken in consideration. In Exodus project, we will investigate the messengers produce by microglia cells considering of their localization e.g. brain regions vs. spinal cord. We want to see if microglia can be divided into sub-populations present in different brain territories where they exert specific functions due to the cellular microenvironment especially in spinal cord, cortex and hippocampus. Cross-talk between microglia with astrocytes though EVs will be investigated in regards of Nobody and Neurobridge projects.
Murgoci AN, CizkovA D, Majerova P, Petovova E, Mevecky L, Fournier I, Salzet M (2018) Brain-Cortex Microglia-Derived Exosomes : Nanoparticles for Glioma Therapy ChemPhysChem 22;19(10):1205-1214 Download PDF