Research team

Laboratory for Experimental Hematology (LEH)

Expertise

Primary cell culture from mouse and human, including immune cells (dendritic cells, macrophages, T-cells) and stem cells (embryonic stem cells, induced pluripotent stem cells, neural stem cells and mesenchymal stem cells). Multi-colour flow cytometric analyses for cellular phenotyping and T-cell analysis. Multi-colour immunocytochemical analyses of cultured (stem) cell populations. Ex vivo genetic engineering of (stem) cell populations using mRNA, plasmid DNA, transposons and lentiviral vectors. Animal models of neuro-inflammation, including the experimental autoimmune encephalomyelitis (EAE) and the cuprizone (CPZ) mouse models applicable for multiple sclerosis research. Cell grafting in brain and spinal cord of rodents. Generation of bone marrow chimeric mice. In vivo non-invasive bioluminescence imaging (monitoring stem cell survival) and magnetic resonance imaging (monitoring white matter lesions). Multi-colour and quantitative immunohistochemical (-fluorescence) analysis of neuro-inflammation.

Immunological control of Varicella zoster virus (VZV)-infected iPSC-derived brain models by steady-state and immune-compromised astrocytes and microglia. 01/01/2021 - 31/12/2024

Abstract

Varicella zoster virus (VZV) is a member of the herpesvirus family and is a highly successful and ubiquitous human pathogen. Both in children and in adults, varicella-related complications may lead to hospitalisation. While in children direct neurological complications may occur following primary infection (varicella), in adults vasculitis and neurological complications are not uncommon following reactivation of latent VZV (herpes zoster). With a clear link between VZV and neuropathology, it is inevitable that the immune system of the central nervous system (CNS) will be challenged by VZV. However, to date little is known about how astrocytes and microglia behave upon encounter of VZV in the CNS. In this project, we will address this question using an established human in vitro model of axonal infection of human induced pluripotent stem cell (hiPSC)-derived CNS neurons with fluorescent reporter VZV stains. Using this model, we will first longitudinal monitor how hiPSC-derived astrocytes and microglia influence the processes of VZV infection, latency and reactivation. Next, using iPSC models derived from VZV patients with mutations in POLRIII, we will investigate whether immune compromised astrocytes and/or microglia can control neuronal VZV infection. Altogether, these studies will help us understanding innate immune control of VZV in the CNS, and will allow - beyond the scope of this project – to develop novel strategies to prevent VZV spreading in the CNS.

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Research team(s)

Deep phenotyping of cellular heterogeneity and maturation in human iPSC-derived brain organoids and cardiomyocytes. 01/01/2021 - 31/12/2024

Abstract

Pluripotent stem cell (PSC) technology is increasingly gaining interest for modelling diseases and developing precision therapeutics. However, the immaturity and heterogeneity of PSC-derived cell populations impinge on the reproducibility and preclude their use for comparative and diagnostic analyses. Recognizing these caveats for their own human induced (hi)PSC-based research, the Laboratories of Experimental Hematology, Cardiogenetics and Cell Biology and Histology have teamed up to develop a pipeline that enables accurate phenotypic staging of hiPSC-derived cell culture models. Specifically, to create mature and standardized 2D and 3D-models for cardiomyocyte cultures and brain organoids, our consortium proposes to optimize the culture conditions and refine the interrogation methods. Longitudinal follow-up and validation of functional activity in the differentiation products will be achieved by means of high-throughput multi-electrode array recordings and live cell calcium and voltage imaging. In parallel, cellular heterogeneity will be mapped with quantitative immunofluorescence and transcriptome analyses. The correlation of functional and molecular readouts will allow establishing a biomarker panel for mature hiPSC-derived cardiomyocyte models and brain organoids. Thus, with this work, we intend to develop more reproducible models and to allow selecting only those with the highest functional maturity, a prerequisite for our future stem cell research aimed at studying and treating neuro-inflammatory and cardiogenetic disorders.

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Upgrade of 9.4T Bruker BioSpec MRI imaging system to Avance NEO hardware architecture. 01/05/2020 - 30/04/2024

Abstract

Upgrade of the hardware of existing equipment (9.4T MRI system from Bruker) to perform state of the art MRI investigations in the brain of small animals such as mice, rats and birds. This hardware upgrade will enable implementation of all new Bruker software packages.

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Multi-well microelectrode array (MEA): a bridge to highthroughput electrophysiology. 01/05/2020 - 30/04/2024

Abstract

This project aims to upgrade the current electrophysiology technologies at UAntwerpen by acquiring a state-of-the-art MicroElectrode Array platform (MEA). To study the electrophysiological properties of excitable cells, currently patch-clamping is the gold standard. However, this is an extremely labour-intensive and invasive technique, limited to short-term measurements of individual cells at single time points. On the other hand, MEAs enable high-throughput non-invasive longitudinal real‐time measurements of functional cellular networks, without disrupting important cell-cell contacts, and thus provide a more physiologically relevant model. The multi-well format allows repeated recordings from cell cultures grown under various experimental conditions, including the opportunity to rapidly screen large drug libraries. Based on these advantages, multi-well MEAs are the most suitable instrument for functionally elucidating the pathomechanisms of neurological/cardiac disorders by performing (1) cardiac activity assays: measurement of field and action potentials from (iPSC-)cardiomyocytes to investigate wave-form, propagation and irregular beating; (2) neural activity assay based on three key measures: frequency of action potential firing, synchrony as measure for synaptic strength and oscillation as hallmark for neuronal organization in time; (3) (iPSC-)vascular smooth muscle contractility assay based on impedance alterations.

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Novel Biomaterial-based Device for the Treatment of Progressive MS - An Integrated Pan- European Approach (PMSMatTrain). 01/05/2019 - 30/04/2023

Abstract

PMSMatTrain is focusing on gaining a comprehensive understanding of the progressive (late degenerative phase) of multiple sclerosis (PMS) from basics to translation, fully supported by 8 beneficiaries (6 research institutions, 2 SMEs). Recruited ESRs will receive compulsory discipline-specific, generic and complementary transferable skills training. PMSMatTrain's Joint Research Education and Training programme (JRTP) will provide early stage researchers with high quality research and transferable skills training in intellectual property, leadership skills, innovation, regulatory affairs, entrepreneurship, gender policy, and medical device evaluation, which will ensure that they are immediately employable in industry. The consortium will develop a multi-modal hyaluronan-based medical device designed to release small molecular weight anti-inflammatory molecules (APRIL and sPIF) followed by remyelination and neuroprotective drugs (ibudilast and miconazole). PMSMatTrain will for the first time utilise these functionalised multi-modal biomimetic hyaluronan scaffolds as a tool to investigate cross-talk between signals arising due to chronic neuroinflammation and those leading to demyelination and axonal loss, while identifying molecular mechanisms that facilitate remyelination and neuroprotection in PMS. This approach could yield the first cortex-proximal and directed biomaterials-based disease-modifying therapy for PMS. These scaffolds will be tested in state of the art MS patient induced stem cell-derived oligodendrocyte cultures and organotypic cultures to investigate MS pathophysiology. In vivo responses will be characterised using field-leading MRI and mass spectrophotometry protocols. PMSMatTrain will also generate a clinically-relevant in silico model of drug elusion and dispersal within the CNS. Our industry partners will develop the end-device by providing standardised manufacturing protocols for scaled-up production and commercialisation of the cGMP product.

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Inner ear gene therapy to prevent deafness in DFNA9. 01/10/2018 - 30/09/2022

Abstract

Hearing loss has a significant impact on quality of life and society in general. Hearing impairment is the most frequent sensory deficit in human populations, affecting 360 million people worldwide. It was listed by the World Health Organization as one of the priority diseases for research into therapeutic interventions to address public health needs. DFNA9 is a dominant hereditary disorder, caused by heterozygote mutations in the COCH gene, which progressively leads to bilateral deafness and balance loss by the age of 50-70 years. Currently, no treatment is available to prevent hearing loss or balance loss in DFNA9 patients. Local gene therapy to restore hearing or prevent hearing loss has been studied in neonatal mouse models for several years. Currently, a clinical study is ongoing in adult patients with profound hearing loss to restore hair cells by injecting virus-based vectors -carrying correcting genetic information- directly into the inner ear. In this project, we aim to generate an inner ear gene therapy tool to prevent hearing loss in a pre-clinical mouse model of DNFA9. Using Adeno-associated virus (AAV)-based vectors, we will apply CRISPR-Cpf1 genome engineering technology to target directly within in the cochlea Coch genomic DNA in a safe and effective way in order to disrupt expression of the mutant (and wild type) Coch protein before onset of disease. Hereby, we expect to reduce or prevent DNFA9-associated sensorineural hearing loss.

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Research team(s)

Development of next-generation 3D brain organoids for the study and modulation of immunemediated neurodegeneration in cerebrovascular disease. 01/01/2018 - 31/12/2022

Abstract

Developing novel neuroprotective and/or immune-modulating therapeutic strategies for almost every neurological disease or trauma requires, both for academia and pharmaceutical industry, the existence of robust in vitro cell culture models to mimic disease-associated pathological events. Unfortunately, a complex interplay between multiple central nervous system (CNS) cell types and multiple cell types from the body's peripheral immune system, cannot be easily recapitulated by currently used 2-dimensional (2D) co-culture assays. It is exactly therefore that successful pre-clinical experimental efficacy has proved to be very difficult to translate into clinical benefit, and as a consequence there is an increasing gap in knowledge and progress between bench and bed side. One highly promising novel approach to improve the predictive power of in vitro human neuro-immune research consists in developing modular 3D brain organoids that resemble brain tissue at the structural, cellular and functional level. Within this project we aim to develop and optimize a new method for generating isogenic 3D brain organoids, comprising human pluripotent stem cell (hPSC)-derived neurons, astrocytes and microglia. Furthermore, hPSC-derived astrocytes and endothelial cells will be used to create a blood-brain-barrier model for physical separation of hPSC-derived macrophages from the generated human 3D brain organoids. Together, this integrated cell system will represent a powerful new 3D human neuro-immune cell culture paradigm. Within this multidisciplinary IOF-SBO project, the methodological approach to generate 3D brain organoids, combined with the experience in the field of clinical research and the availability of patient samples, is truly unique and will - in first instance - highly contribute to the field of in vitro cerebrovascular disease modelling and treatment validation. Furthermore, our aims to install an integrated 3D brain organoid technology platform at the University of Antwerp, will - given the current scientific and economic interests – allow for both short-term and long-term valorisation of our combined efforts, with both intellectual (PhD-theses, A1 publications) as well as financial (contract research) revenues.

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Human and murine macrophages with a stable alternative activation as a therapeutic tool to promote neuroregeneration. 01/01/2018 - 31/12/2021

Abstract

Worldwide, spinal cord injuries (SCI) are a major cause of morbidity, mortality and reduced quality of life. Until now no regenerative therapy for SCI is available and standard care of SCI patients includes primarily the administration of immunosuppressant drugs and rehabilitation. Thus, new therapeutic strategies are desperately needed. After SCI, pro-inflammatory macrophages dominate the spinal cord and exert detrimental effects by secreting multiple pro-inflammatory factors, by stimulating the formation of the inhibitory fibrotic scar, and by attacking dystrophic axons. Previously, the applicants demonstrated that the implantation of IL-13-expressing mesenchymal stem cells or macrophages induces 'antiinflammatory' arginase-1 (Arg-1)-positive macrophages/microglia in the injured spinal cord, leading to improved functional recovery. Therefore, we investigate here whether high Arg-1 production by macrophages with a stable alternative activation leads to the suppression of pro-inflammatory macrophages/microglia after SCI via arginine depletion. In addition, for translation to the human situation, we will investigate whether Arg1-overexpressing human macrophages exert neuroprotective effects in an in vitro multicellular co-culture model of human stem cell-derived corticospinal-like motor neurons, astrocytes and microglia. Thus, in this project, we aim to analyse one key mechanism of how anti-inflammatory macrophages improve functional recovery after SCI.

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Development of isogenic human embryonic stem cell-derived 3D neuro-immune cell culture models: pre-clinical evaluation of interleukin 13 for microglia and macrophage immunomodulation under stroke-like pathology. 01/10/2017 - 30/09/2021

Abstract

Development of three-dimensional (3D) in vitro cell culture models for human neuro-immunological research is currently a hot topic in medical cell biology research. Although multiple protocols have been described for generating human 3D brain organoids starting from pluripotent stem cells, current models display several limitations, including the lack of extracellular matrix (ECM), the absence of multiple types of immune cells and a functional blood-brain-barrier (BBB). With this project we aim to develop and optimize a new method for generating 3D neuro-immune cell culture models to study and modulate human neuro-inflammatory responses. For this, isogenic 3D cell cultures comprising human embryonic stem cell (hESC)-derived neurons, astrocytes and microglia will be established on decellularized mouse brain sections in order to provide growth and organizational support by original brain ECM proteins. In addition, hESC-derived astrocytes and endothelial cells will be used to create a BBB model for physical separation of hESC-derived macrophages. Further inclusion of genetic engineering strategies, to allow for real time bioluminescence imaging and (live cell) confocal microscopy, will be applied to ensure profound validation and high throughput screening applications. Once established, we will use this technology to further extend our research efforts to optimize therapeutic strategies based on interleukin (IL)13-mediated immunomodulation, following hypoxic and hypoglycemic stress (i.e. stroke-like conditions). Once validated, we believe that implementation of the proposed 3D brain organoid technology by academia and/or pharmaceutical industry will not only have great impact on the reliability of pre-clinical drug screening, and consequently on the medical and social investments associated with patient care, but also will find application in advanced human toxicology research.

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Development of allele-specific CRISPR-nuclease gene therapy for late-onset sensorineural hearing impairment in a new humanized DFNA9 mouse model. 01/01/2020 - 31/12/2020

Abstract

Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. At current, it is believed that the presence of aberrant COCH proteins in the extracellular matrix (ECM) of the inner ear leads to local cell damage resulting in progressive hearing loss. Within Belgium and the Netherlands, there are > 1000 patients affected by the P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness and balance loss. Furthermore, there are over twenty different COCH mutations identified in people from all over the world that lead to SNHL. Given the genetic nature of this disorder with highly specific mutations, as well as recent advances in CRISPR-nuclease mediated gene therapeutic approaches, there is a great opportunity to develop a successful therapeutic strategy to reduce or prevent DFNA9-induced SNHL.

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A human in vitro demyelination model for studying the effect of M2 macrophages/microglia. 01/01/2019 - 31/12/2020

Abstract

The host's laboratory's promising results of IL13 treatment in a mouse model for MS, encourage us to further investigate this potential therapeutic strategy in a human setup. Therefore, we propose to develop a human in vitro demyelination model to study the effect of IL13-induced M2 macrophages and microglia. We will do so by (I) differentiating hiPSC towards oligodendrocytes; (II) evaluating the myelinating potential by oligodendrocyte-neuron co-culture; (III) optimizing a toxin-induced demyelination procedure; and (IV) evaluating the effect of macrophage/microglia addition with or without IL13 stimulation.

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Application of human 3D brain organoids to evaluate the potency of interleukin 13 for modulation of detrimental microglia and macrophage immune response. 06/12/2017 - 31/12/2019

Abstract

Due to the current understanding that multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), where mononuclear cell infiltration in brain and spinal cord is a major contributor to demyelination, gliosis, axonal loss and eventually loss of neuronal function, we investigated over the past 6 years whether local modulation of CNS lesions with the immune-modulating cytokine interleukin (IL)13 might ameliorate detrimental disease progression. While our pre-clinical studies in the cuprizone (CPZ)-induced CNS inflammation/demyelination mouse model for human MS have demonstrated proof-of-principle for this approach, currently we do not know whether human microglia and macrophages are equally well susceptible to IL13-mediated immunomodulation in the pro-inflammatory MS environment. Using advanced human induced pluripotent stem cell (hiPSC) derived 3D cell culture models, we aim to provide further pre-clinical rationale for the use of IL13 as an additional treatment approach in advanced stage MS.

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Gene Therapy for DFNA9 : downregulating the mutant COCH gene in mammalian cell lines by uising a synthetic adeno-associated viral vector Anc80L65 and CRISPR/Cas9-mediated genetic editing. 01/11/2017 - 31/10/2018

Abstract

DNFA9 is a cause of autosomal dominant (AD) non-syndromic late-onset sensorineural hearing loss (SNHL) associated with progressive bilateral vestibular failure (BVF). The age of SNHL onset varies depending on the mutation though the average onset age lies around 3rd-5th decade. It typically starts as downsloping of the audiogram at the age of onset and evolution towards deafness. DFNA9 is caused by mutations in the COCH gene (Coagulation Factor C Homology), which is located on chromosome 14q12-13 and encodes for a 550 amino acid protein, cochlin, which is expressed throughout the inner ear in spindle-shaped cells located along nerve fibers between the spiral ganglion and sensory epithelium. Over twenty mutations have been identified in regions, including North America, Japan, Australia, Korea, China and Belgium/Netherlands. Our objective is to establish an in vitro proof-of-principle for a gene therapeutic approach that targets mutant cochlin expression in the inner ear using Anc80L65AAV/CRISPR/Cas9-mediated gene editing. We hope to establish in vitro that this technique enables specific correction or downregulation of the mutant COCH gene in mammalian cell lines without modulating the normal COCH allele, which is still present in this heterozygous disorder. This work can provide proof-of-concept for in vivo studies in transgenic heterozygous COCH mice targeting the mutated COCH gene by means of an AAV.

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Research team(s)

Development of isogenic human embryonic stem cell-derived 3D neuro-immune cell culture models: pre-clinical evaluation of microglia and macrophage immunomodulation for stroke treatment. 01/10/2017 - 30/09/2020

Abstract

Development of three-dimensional (3D) in vitro cell culture models for human neuro-immunological research is currently a hot topic in medical cell biology research. Although multiple protocols have been described for generating human 3D brain organoids starting from pluripotent stem cells, current models display several limitations, including the lack of extracellular matrix (ECM), the absence of multiple types of immune cells and a functional blood-brain-barrier (BBB). With this project we aim to develop and optimize a new method for generating 3D neuro-immune cell culture models to study and modulate human neuro-inflammatory responses. For this, isogenic 3D cell cultures comprising human embryonic stem cell (hESC)-derived neurons, astrocytes and microglia will be established on decellularized mouse brain sections in order to provide growth and organizational support by original brain ECM proteins. In addition, hESC-derived astrocytes and endothelial cells will be used to create a BBB model for physical separation of hESC-derived macrophages. Further inclusion of genetic engineering strategies, to allow for real time bioluminescence imaging and (live cell) confocal microscopy, will be applied to ensure profound validation and high throughput screening applications. Once established, we will use this technology to further extend our research efforts to optimize therapeutic strategies based on interleukin (IL)13-mediated immunomodulation for cerebrovascular disease.

Researcher(s)

Research team(s)

Generation of iPSC-derived 3D neuro-immune cell culture models for study and modulation of neuro-inflammatory processes. 01/01/2017 - 31/12/2020

Abstract

Development of three-dimensional (3D) in vitro cell culture models for neuroscience research is currently a hot topic in medical cell biology research. Although multiple protocols have been described for generating 3D brain organoids starting from pluripotent stem cells, current models display several limitations, including the lack of extracellular matrix (ECM) and the absence of glial and immune cells. With this project we aim to develop and optimize a new method for generating 3D neuro-immune cell culture models to study and modulate neuro-inflammatory responses. For this, 3D cell cultures comprising induced pluripotent stem cell (iPSC)-derived neurons, astrocytes and microglia will be established on decellularized mouse brain sections in order to provide growth and organizational support by the original brain ECM. Further inclusion of genetic engineering strategies, to allow for real time bioluminescence imaging and live cell confocal microscopy, will be applied to ensure high throughput screening applications. Once established, we will use this technology to further extend our research efforts to optimize therapeutic strategies based on interleukin (IL)13-mediated immunomodulation, following hypoxic and hypoglycemic stress. Once validated, we believe that implementation of this technology by pharmaceutical industry will have great impact on the reliability of pre-clinical drug screening, and consequently on the medical and social investments associated with patient care.

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Research team(s)

Unravelling the role of neuroglobin in neuroprotection and neuroplasticity. 01/10/2016 - 30/09/2018

Abstract

The general objective is to obtain insight in the contribution and working mechanism of two vital processes in the brain: 1) neuroprotection and 2) 17β-estradiol (E2) induced neuroplasticity. As we aim to focus on different expression patterns of Ngb both in vitro and in vivo, the first objective is to improve valid Ngb overexpressing and knock-out (KO) systems.

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Modular confocal microscopy platform with light sheet illumination. 01/05/2016 - 30/04/2020

Abstract

The application concerns an innovative microscopy platform for visualizing cells, tissue specimen and living small model organisms in three dimensions at unprecedented speed and with excellent resolution and contrast. As a unique feature, the platform is equipped with a light-sheet module, which is based on an orthogonal configuration of laser-generated, micrometer-thin plane illumination and sensitive one-shot detection. Seamless integration with confocal modalities enables imaging the same sample from the micro- to the mesoscale. The device has a broad application radius in the neurosciences domain inter alia for studying neurodegeneration and -regeneration (e.g. whole brain imaging, optogenetics); but it also has direct utility in various other fields such as cardiovascular research (e.g. plaque formation and stability), plant developmental research (e.g. protein localization during plant growth) and ecotoxicology (e.g. teratogenicity and developmental defects in zebrafish). Furthermore, its modular construction will enable adaptation and targeted expansion for future imaging needs.

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Improving the efficacy of peripheral anti-glioma vaccination by local modulation of the tumour's immunosuppressive microclimate. 01/10/2015 - 30/09/2018

Abstract

In this doctoral research proposal, we propose to combine both innate and adaptive immune stimulation approaches in order to mount a more potent anti-tumour response. In addition, an in-depth characterisation of central nervous system and peripheral immune changes will be performed following tumour induction and/or anti-tumour vaccination. With this research project we therefore aim to contribute to a better understanding of cellular interactions in the events of tumour growth and eradication, and to the improvement of current immunotherapeutic interventions of GBM.

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    Unravelling the cellular and molecular determinants of neuroprotection following implantation of interleukin 13-expressing mesenchymal stem cells in inflammatory brain tissue. 01/10/2015 - 31/12/2016

    Abstract

    Detrimental inflammatory responses in the central nervous system (CNS) are a hallmark of various neurodegenerative pathologies, with multiple sclerosis (MS) and stroke/trauma being excellent examples demonstrating the highly complex interplay between CNS resident microglia and lesion infiltrating leucocytes. Lesion-associated inflammatory responses, both in the acute as well as in the chronic phase, are classified as being highly pro-inflammatory. In this context, it is generally believed that a functional conversion of a pro-inflammatory type M1 microglia/macrophage phenotype, which can readily be detected in severe CNS inflammatory lesions, into a type M2a immune modulating microglia/macrophage phenotype can have a beneficial effect on disease outcome. Using our extensive experience with cell implantation into the CNS of mice, our current research aims at in vivo modulation of neuro-inflammatory responses by intracerebral implantation of mesenchymal stem cells (MSCs) genetically engineered to express interleukin (IL)13, a potent inducer of the M2a phenotype in macrophages. Thus far, we have demonstrated in the cuprizone (CPZ) mouse model of CNS inflammation and demyelination that microglial quiescence and subsequent protection against demyelination coincides with the appearance of M2a-polarised macrophages in the CNS following grafting of IL13-expressing MSCs. Continuing our research, this PhD project will focus on unravelling the in vivo signalling events that lead to IL13-mediated induction of the M2a macrophage phenotype within MSC graft-infiltrating macrophages in the CNS, as well as the cellular interactions by which these M2a macrophages can influence the development of microglia/macrophage-mediated neuro-inflammation in the CNS. Upon completion we hope to: (i) further elucidate the immunological consequences of MSC grafting in the CNS, and (ii) provide pre-clinical rationale for the use of IL13 as an immune modulating cytokine in the CNS.

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      Neuro Image-guided decoding of mechanisms involved in healthy, accelerated and pathological aging. 01/01/2015 - 31/12/2018

      Abstract

      The overall goal of project is to contribute new information that will greatly increase our understanding about underlying mechanisms of hypothalamus-driven normal, accelerated and pathological aging of the brain, with the focus on structural alterations and subsequent alterations of specific functional networks such as the default mode network (DMN) and its anticorrelated networks. Our results will provide fundamental knowledge for age dependent intrinsic network structural changes as a reference for pathological aging studies where altered DMN activity needs to be reliably differentiated from that observed in healthy aging.

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      In vivo interleukin-13 mRNA gene therapy for modulation of neuroinflammatory lesions : a pre-clinical proof-of-concept study in the cuprizone mouse model of multiple sclerosis. 01/01/2015 - 31/12/2017

      Abstract

      This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

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        Image-guided decoding of mechanisms involved in healthy, accelerated and pathological aging. 01/10/2014 - 30/09/2017

        Abstract

        Aging has profound effects on many cellular processes that predispose to neurodegeneration, impairment in cognitive function, as well as changes in brain functional connectivity networks (e.g. default mode network) and synaptic alterations. However, the key mechanisms orchestrating brain aging remain largely unknown. More and more findings in rodents and humans have established that inflammatory processes in the hypothalamus can contribute to neurodegeneration upon aging via reproductive (HPG) axis. However, the exact mechanisms by which (i) Inflammatory signalling in the hypothalamus contributes to the occurrence of age-related functional connectivity and synaptic alterations, and (ii) hypothalamic HPG signalling modulates age-related neurodegeneration and cognitive changes are not well understood and need further investigation. The main goals of this project are to investigate: (i) how deregulation of the HPG axis impacts brain networks that display aging decline, (ii) how hypothalamic inflammation is steering deregulation of HPG axis in healthy aging, accelerated aging and pathological aging, and (iii) how hypothalamic inflammatory responses become activated upon healthy, accelerated and pathological aging, with specific focus on cellular, connectional architecture of functional networks. This project will contribute new information that will greatly increase our understanding about underlying mechanisms of hypothalamus-driven systematic aging of the brain.

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        Unravelling the role of neuroglobin in neuroprotection and neuroplasticity. 01/10/2014 - 30/09/2016

        Abstract

        The general objective is to obtain insight in the contribution and working mechanism of two vital processes in the brain: 1) neuroprotection and 2) 17β-estradiol (E2) induced neuroplasticity. As we aim to focus on different expression patterns of Ngb both in vitro and in vivo, the first objective is to improve valid Ngb overexpressing and knock-out (KO) systems.

        Researcher(s)

        Research team(s)

        Postdoctoral research dr. Prim Singh. 01/12/2013 - 30/03/2014

        Abstract

        This project represents a formal research agreement between UA and on the other hand BBSRC. UA provides BBSRC research results mentioned in the title of the project under the conditions as stipulated in this contract.

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        Research team(s)

          Improving efficacy of peripheral anti-glioma vaccination by local modulation of the tumour's immunosuppressive microclimate. 01/10/2013 - 30/09/2015

          Abstract

          In this doctoral research proposal, we propose to combine both innate and adaptive immune stimulation approaches in order to mount a more potent anti-tumour response. In addition, an in-depth characterisation of central nervous system and peripheral immune changes will be performed following tumour induction and/or anti-tumour vaccination. With this research project we therefore aim to contribute to a better understanding of cellular interactions in the events of tumour growth and eradication, and to the improvement of current immunotherapeutic interventions of GBM.

          Researcher(s)

          Research team(s)

            Transgenic reporter animal collection for experimental research (TRACER). 06/06/2012 - 31/12/2013

            Abstract

            TRACER: Transgenic Reporter Animal Collection for Experimental Research. Tracer will consist of a widespread variety of transgenic reporter mice, which directly fit within the research aims of two (bio)medical frontline research domains of the University of Antwerp, namely "Neurosciences" and "Imaging".

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              Functional identification of innate immune responses following stem cell implantation in the central nervous system of mice. 01/10/2011 - 10/04/2013

              Abstract

              In this PhD project we aim to completely characterize the migration behaviour, fate and physiology of different stem cell types following administration in the 'experimental autoimmune encephalomyelitis' (EAE) mouse model for Multiple Sclerosis. A combination of in vivo (BLI and MRI) and post-mortem (histology) imaging modalities will be used to reveal different cell characteristics and compare these characteristics between the different cell types included in this study. These results will enable us to effectively modify stem cell populations in order to enhance possible therapeutic effects (e.g. enhanced migration towards target sites and increased survival of grafted stem cells).

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              Neural Stem Cells: molecular and physiological control of in vivo migration and differentiation. 01/01/2011 - 31/12/2014

              Abstract

              This proposed multidisciplinary research consortium, consisting of 6 different laboratories from the University of Antwerp, aims to understand the cellular and/or functional interactions of NSC implants in healthy and injured neural tissue (cuprizone-mediated demyelinisation mouse model). With this research project, which focuses on the in vivo molecular and physiological control of NSC, we aim to contribute to the in vivo study and modulation of NSC migration, survival, differentiation and functional integration.

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                Immunomodulatory therapy for spinal cord injury via IL-4 en IL-13 secreting stem cells. 01/01/2011 - 31/12/2014

                Abstract

                The aim of this research project is to investigate the effect of IL-4 and IL-13 delivered by locally applied autologous neural stem cells (NSC) on axon regeneration after traumatic CNS injury using both in vitro as well as in vivo models.

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                  Control of glioblastoma by modulation of the brain's innate immune responses. 01/01/2011 - 31/12/2014

                  Abstract

                  We first aim to identify and functionally describe immune-suppressive proteins and/or signalling molecules on glioma cells, which lead to inhibition of microglia. Then, we will develop strategies to modify microglia in order to prevent inhibition by glioma cells in vitro and in vivo. We specifically aim to genetically engineer microglia with 'short interfering RNAs' against receptors or signalling molecules involved in immune inhibition by GL261 cells in order to improve their cellular therapeutic potency.

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                    Characterisation of innate immune responses in the central nervous system: modulation towards immunological acceptance of allogeneic cellular grafts. 01/01/2011 - 31/12/2014

                    Abstract

                    In this project, we aim to further elucidate the mechanisms leading to immune-mediated rejection of allografts in the CNS. For this, we will non-invasively (by in vivo bioluminescence imaging) identify the exact timing and degree of microglia immune-reactivity in relation to immune-mediated rejection of different allogeneic adult-, embryo- and placenta-derived cell populations.

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                      'Molecular Imaging' meets 'Imaging Molecules' 01/07/2010 - 30/06/2014

                      Abstract

                      Magnetic Resonance imaging plays a crucial role in stem cell research in order to investigate whether administered stem cells are able to migrate to the target organ, locally survive, differentiate and contribute to regenerated tissue. However, knowledge regarding the interaction of MRI contrast agents with (sub)cellular structures is lacking. In this project, we will use advanced TEM techniques to investigate different MRI contrast agents and loading techniques for neural stem cells.

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                      Neural stem cells: molecular and physiological control of in vivo differentiation, migration and immunogenicity. 01/10/2009 - 30/09/2012

                      Abstract

                      Future research will be focussed on three main topics: 1) Characterization of neural stem cells. While culture conditions have recently been established for adherently growing NSC, many questions remain regarding: (a) optimal growth conditions, (b) identity, and (c) differentiation potential in vitro and in vivo. 2) In vivo migration and survival of neural stem cells. While NSC-based therapies have demonstrated beneficial outcome in animal models of neurotrauma and/or -inflammation, currently there is no detailed knowledge regarding in vivo survival, migration and function of transplanted NSC. 3) Immunobiology of neural stem cells. While NSC-based therapies are being developed worldwide in various animal models, currently there is no knowledge regarding the in vivo interaction between the brain's innate/adaptive immune system and allogeneic NSC implants.

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                        Clinical and preclinical research of the effect of cellular mediators on the modulation of pathogenic responses in multiple sclerosis. 01/01/2009 - 31/12/2012

                        Abstract

                        In this project, we want to further investigate and exploit the capacity of DC and Treg to correct or modulate pathogenic responses in MS patients. Current research will provide the foundation for the eventual development of a cellular vaccine for the treatment of MS. Depending on the results of this study it can be envisaged to treat patients suffering from MS with tolerogenic DC and/or immunosuppressive Treg in order to eliminate or inactivate autoreactive T cells.

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                          Characterization of immune responses against allogeneic stem cell implants in the central nervous system. 01/01/2009 - 31/12/2011

                          Abstract

                          In this project, we will investigate the role of innate (microglia) and adaptive (T-cells) immune responses leading to immunological rejection of allogeneic stem cell implants in the central nervous system of immunocompetent mice.

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                            Development of combined magnetic resonance imaging and bioluminescence imaging to study stem cell migration and survival in mouse brain after neurotrauma. 01/10/2008 - 30/09/2009

                            Abstract

                            In this study, we aim to investigate whether genetic modification of exogenous stem cells with chemokine receptors enhances their migration towards lesions in brain tissue. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) technology will be used and validated to visualize migration and survival of grafted stem cells in vivo.

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                            CRYo-banking of stem cells for human therapeutic application. (CRYSTAL) 01/02/2007 - 31/01/2010

                            Abstract

                            In this EU project, partners UA (Antwerp) and KUL (Leuven) will investigate whether transient genetic modification of cord blood and bone marrow hematopoïetic stem cells with mRNAs encoding transcription factors, growth factors and receptors (all involved in self-renewal and migration of stem cells) results in improved in vivo repopulation of SCID mice. This research will lead to improved methodology for hematopoietic stem cell transplantation in adults and children.

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                              Development of reporter gene imaging for MRI and BLI assessment of migration and survival of transplanted mesenchymal and neural stem cells after traumatic brain injury in mice. 01/10/2006 - 30/09/2010

                              Abstract

                              Stem cell transplantation after neurotrauma is a promising field of research in current biomedical research. However, to date, little is known about successful migration and survival of transplanted stem cell populations on site of trauma. This project aims to develop genetically modified adult and embryonic stem cell populations which can be assessed by MRI and BLI after transplantation in traumatised mouse brain.

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                              Transplantation of embryonic stem cell-derived neural stem cells after spinal cord and traumatic brain injury. 01/10/2006 - 30/09/2009

                              Abstract

                              This project will investigate whether transplantation of defined embryonic stem cell-derived neural stem cells (ES-NSC), genetically modified to secrete neurotrophic factors, can support or improve recovery after TBI and SCI. An improved recovery can be due to: A) a decreased secondary neural loss due to secretion of neurotrophic factors, and/or B) an enhanced neural recovery due to functional integration of transplanted ES-NSC and/or recruited endogenous NSC.

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                                Exploring the functional and histological recovery of damaged neural tissue after traumatic spinal cord injury in rat: modulation by in vivo transplantation of in vitro transfected adult mesenchymal and embryonic stem cells. 01/10/2006 - 30/09/2007

                                Abstract

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                                Modulation of immune responses directed against allogeneic cell transplants in mouse brain . 01/07/2006 - 31/12/2010

                                Abstract

                                Transplantation of embryonic stem (ES) cell-derived neural progenitor cells (ES-NPC) will become an important option for treatment of neurological trauma . However, due to technical limitations, such transplantations will most likely be using NPC derived from allogeneic ES cells. This project investigates different immunological strategies in order to overcome rejection of transplanted murine ES-NPC in brain of MHC-mismatched mice.

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                                  Transplantation of adult and embryonic stem cells genetically modified with neurotrophic factors after traumatic brain injury in mice. 01/05/2005 - 31/12/2006

                                  Abstract

                                  Neurological trauma after sport, work or traffic accidents frequently lead to morbidity and mortality among adults and children. A promising therapy for neurological injury is stem cell transplantation. This project will investigate whether transplantation of adult and embryonic stem cells, genetically modified with neurotropic factors, might improve recovery after traumatic brain injury in mice.

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                                    Exploring the functional and histological recovery of damaged neural tissue after traumatic spinal cord and brain injury in mice : modulation by in vivo implantation of in vitro transfected embryonic stem cells. 01/10/2004 - 30/09/2006

                                    Abstract

                                    Currently, there is no effective therapeutical approach for central nervous system injuries (both brain and spinal cord injury). Our research project will focus on 1) the tranplantation of embryonic stem cell-derived neural cell types in order to replace the damaged neural tissue, and 2) the transplantation of adult stem cells genetically modified in order to produce neurotrofic factors for regeneration of damaged neural tissue. Our project will be divided into two parts: a spinal cord injury model and a traumatic brain injury model. For the spinal cord injury model, a surgical transsection will be made on the spinal cord of rat, followed by tranplantation of both non- and gene-modified adult/embryonic stem cells at different time points in the injured spinal cord. Functional recovery will be monitored using the BBB-score for evaluation of locomotor function. For the brain injury model, induced via a weight impaction on the skull of the mouse, both non- and gene-modified adult/embryonic stem cells will be transplanted at different time points in the injured brain. Functional recovery will be monitored using standarised cognitive and motoric tests

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                                    Differentiation of embryonic stem cells into neural cell types following electroporation with mRNA encoding neural key regulatory genes. 01/01/2004 - 31/12/2005

                                    Abstract

                                    Despite new surgical techniques, pharmacological treatments and functional neurological stimulation methods, brain and spinal cord injuries remain a large medical and social problem. Therefore novel research aims at the development of new therapies reaching further than current revalidation strategies. Stem cell research offers promising opportunities for the development of new methods in order to repair or replace damaged tissues or cells. Stem cells have the potential to differentiate towards a neural phenotype, creating the possibility to replace cerebral or spinal neurons, astrocytes and oligodendrocytes. The goal of this project is to investigate whether embryonic stem cells, both mouse and human, genetically loaded with mRNA encoding neural key regulatory genes can differentiate towards neural cell types in vitro and in vivo (mouse model).

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                                      Use of cultured human dendritic cells loaded with defined or full spectrum tumor antigens for optimal stimulation of in vitro anti-tumor immunity. 01/10/2001 - 30/09/2003

                                      Abstract

                                      Although tumor-specific antigens have been described for a number of cancers, the immune response to these antigens is often inexistent or deficient. One possible explanation for this deficient immune response is that tumor cells themselves do not function adequately as antigen presenting cells (APC). Therefore, gene transfer in dendritic cells (DC), which are very potent antigen presenting cells of the immune system, could be a useful strategy for tumor immunotherapy. In vitro cultured human dendritic cells will be transfected with mRNA encoding tumorassociated/specific geneproducts or uploaded with the full antigenic spectrum of tumorcells (tumorextracts, cellysates or total RNA). After cocultivation with autologeous CD8+ T-ceIls we will investigate if the cultured cytotoxic T-cells show a direct speci-ficity against tumorcells. The main purpose of these experiments is the development of a DC-based in vitro immunotherapy protocol for coloncancer, cervixcancer and lymphomas.

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                                        Use of cultured human dendritic cells loaded with defined or full spectrum tumor antigens for optimal stimulation of in vitro anti-tumor immunity. 01/10/1999 - 30/09/2001

                                        Abstract

                                        Although tumor-specific antigens have been described for a number of cancers, the immune response to these antigens is often inexistent or deficient. One possible explanation for this deficient immune response is that tumor cells themselves do not function adequately as antigen presenting cells (APC). Therefore, gene transfer in dendritic cells (DC), which are very potent antigen presenting cells of the immune system, could be a useful strategy for tumor immunotherapy. In vitro cultured human dendritic cells will be transfected with mRNA encoding tumorassociated/specific geneproducts or uploaded with the full antigenic spectrum of tumorcells (tumorextracts, cellysates or total RNA). After cocultivation with autologeous CD8+ T-ceIls we will investigate if the cultured cytotoxic T-cells show a direct speci-ficity against tumorcells. The main purpose of these experiments is the development of a DC-based in vitro immunotherapy protocol for coloncancer, cervixcancer and lymphomas.

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