Research areas

The Laboratory of Cell Biology and Histology (CBH) is an interfaculty research group, uniting scientists from the Faculty of Biomedical, Pharmaceutical and Veterinary sciences and the Faculty of Medicine and Health Sciences. Their joint mission is to elucidate the cell biological principles of human physiology and disease, so as to expose new entry points for diagnostic and therapeutic strategies.

Core research lines strongly align with key research domains at the University of Antwerp, such as Neurobiology, Oncology, Imaging and Infectious diseases. The research is fueled by solid expertise in cell, tissue and systems biology and finds a common denominator in the use and development of advanced microscopy technology. 

In line with the latter, CBH also operates as the Antwerp Centre for Advanced Microscopy (ACAM), providing high-end microscopy service tailored towards both ultrastructure and live cell-imaging applications. As microscopy hub, CBH is founding member of the Centre of Excellence ‘µNeuro’ and of the former IOF-consortium ‘EGAMI’ and the new IOF-consortium ‘iMARK’ of the University of Antwerp, the University valorisation platform for Imaging.

Key research areas

Translational gut and lung research

Accelerated Aging Diseases

Next-generation Microscopy

Master Thesis Subjects

Immune dysregulation along the gut-brain axis in Alzheimer’s disease
Tutor: Peter Verstraelen - Promoters: Jean-Pierre Timmermans, Winnok De Vos

Recent insights have shattered the traditional view of the brain being an immune-privileged organ, inert to peripheral immunity. Both epidemiological and preclinical studies have shown that the risk of developing Alzheimer’s Disease (AD) and aspects of neurodegeneration can be exacerbated by inflammation in the gut. In this context, we have recently discovered that bacterial amyloids, produced by the enteric microbiome, are potent immune inducers in the gastro-intestinal tract and its enteric nervous system. Herein, serum amyloid A3 (SAA3) emerged as an important regulator that fuels a pro-inflammatory feed-forward response, typified by cytokine secretion and T-cell infiltration. Given its amyloidogenic properties, its long-range, blood-brain barrier-penetrant signaling potential, and elevated levels in AD patient brain, we hypothesize that SAA3 represents an important mediator of pathogenic gut-brain communication in AD. To test this hypothesis, we will make use of an APPnl-g-f/MAPT mouse model and study the release of SAA3 in colon and brain tissue at several time points after the induction of colon inflammation. Using state-of-the-art microscopy and cellular models of the enteric and central nervous system, we will unravel the immune mechanisms that contribute to neurodegeneration in gut and brain.

Key words: Neurodegeneration, Enteric nervous system, Gut-brain axis, Inflammation, Microscopy

Neuro-Immune communication in the gut and meninges during ageing and inflammation
Tutor: Jasper Van Haver - Promoter: Sales Ibiza Martinez

One of the major concerns in gastrointestinal medicine is to understand how the mucosal environment works. The ‘rise’ of enteropathies and neuropathies in developed countries can be attributed to an increasingly ageing population, environmental factors, genetic factors, and/or inadequate dietary habits. The Gastrointestinal (GI) tract is the centre of absorption and secretion, which is essential for growth, digestion, and protection against pathogenic microorganisms. A breakdown of intestinal homeostasis can lead to chronic inflammation, resulting in a decrease or dysfunction of the neurons within the gut wall, impacting gut function and inducing enteric, or central neuropathy. To improve the therapeutic design, we aim to understand how different environments affect neuro-immune communication and how this influences inflammation or health/repair. To achieve this goal, we are identifying the local inter- and intra-cellular networks and which pathways connect with the central neuropathies.

Keywords: Neurodegeneration, Enteric nervous system, Meninges, qPCR, Cell culture, Confocal microscopy, FACS, Bioinformatics

Studying the novel Mrgprb2/X2-mediated signaling pathway as driver of aberrant mast cell functioning in the colon and its resulting effects on visceral hypersensitivity associated with irritable bowel syndrome.
Tutor: Lana Lambeets – Promoter: Jean-Pierre Timmermans, Sales Ibiza Martinez

Mast cells are immune cells that are typically associated with allergic reactions at mucosal surfaces. Here, mast cells form operating units with sensory nerves and can contribute to sensations of itch and pain. In the context of Irritable Bowel Syndrome (IBS), a frequently occurring gastrointestinal disorder characterized by abnormal pain signaling (i.e. visceral hypersensitivity), the involvement of abnormal mast cell functioning has been recognized, but the exact receptors and signaling mechanisms driving this aberrant mast cell functioning remain poorly understood. In this respect, the presence of a novel IgE-independent, ‘pseudo-allergic’ pathway of mast cell activation pathway in the colon, consisting of mouse Mrgprb2 and its human counterpart MRGPRX2, was recently discovered our lab. In this project, we will focus on the specific role of this novel Mrgprb2/X2-mediated signaling pathway as a driver of aberrant mast cell functioning in the pathophysiology of IBS and associated visceral hypersensitivity. In this way, this project might generate a novel paradigm in our understanding of IBS pathophysiology and may form a solid foundation for further studies into the therapeutic potential of this pathway in these conditions.

Keywords: Mast cell, Substance - Mrgprb2/X2 signalling, IBS, in vitro culture, translatome analysis, confocal imaging, VMR recordings, iPSC derived sensory neurons

Single cell-based staging of glioblastoma-infiltration in cerebral organoids
Tutor: Sarah De Beuckeleer – Promoter: Winnok De Vos, Tim Van De Looverbosch

With the advent of human induced pluripotent stem cell (iPSC) technology, it has now become possible to generate organoids that more faithfully capture part of the heterogeneity and three-dimensional context of the human brain. However, the complexity and optical inaccessibility of such tissue mimics hamper their adoption in a routine screening setting. We are developing an approach for in-depth cellular phenotyping of organoids, using multiplex staining, automated light sheet microscopy and deep learning. In this thesis we intend to apply this approach for staging the infiltration of glioblastoma (GBM) cells into cerebral organoids. To this end, we will seed iPSC-derived cerebral organoids with fluorescently labeled GBM cells with different invasive properties onto different types of organoids, ranging from immature to immune-competent. We will track GBM mobility and network formation as a function of time and characterize their cell cycle state, activation status and local context by means of post-hoc immunostaining to better understand the interplay of the GBM cells and the local microenvironment. Finally, we will evaluate the potential of candidate pharmacological agents to selectively interfere with GBM cell infiltration.

Key words: glioblastoma, organoids, morphological phenotyping, image analysis, light-sheet microscopy, deep learning

Tau-induced senescence in human mini-brains
Tutor: Johanna Van Den Daele – Promoter: Winnok De Vos, Johanna Van Den Daele

Defects in the microtubule associated protein tau typify a range of neurodegenerative disorders termed tauopathies, which includes Alzheimer’s disease. Recent studies point to the potential involvement of cellular senescence, an irreversible non-proliferative state, associated with inflammatory cytokine secretion, in disease development. However, the causality, timing, and afflicted cell types remain poorly characterized. The goal of this thesis is to define the exact causal relationship between senescence and tauopathy development in a human context. To achieve this, immune-competent cerebral organoids (containing neurons, astrocytes, and microglia) will be produced from human iPSC and pathology will be triggered by viral transduction and/or seeding of aggregation-prone tau variants. In-depth molecular characterization and microscopy-based spatial proteomics will help defining whether senescence is a driving factor in human tau pathology development.

Key words: Tauopathy, Cell biology, iPSC, senescence, Microscopy

Nuclear envelope stress in laminopathy patient-derived cardiomyocytes
Tutor: Lauran Vandeweyer – Promotor: Winnok De Vos

Dilated cardiomyopathy (DCM) compromises the heart’s essential function of pumping blood through the body and is the primary cause of heart transplants worldwide. Hereditary variants of DCM are driven by mutations in the LMNA gene, which encodes A-type lamins, crucial components of nuclear envelope (NE). Lamin perturbations predispose cells for nuclear dysmorphy and NE rupture, which compromises cell homeostasis and elicits DNA damage. We hypothesize that this so-called NE stress represents a common hallmark of cardiac laminopathies. To investigate the impact of pathogenic lamin variants on this process in a relevant context, we are generating induced pluripotent stem cell-derived cardiomyocytes from cardiac patient fibroblasts harboring specific LMNA mutations as well as precision knockouts. In the context of this thesis, we will analyze the fitness and contractile function of these cells in relation to the composition and mechanical resilience of the NE. We will validate defects in 3D cardioids and in patient biopsies. This way, we intend to expose the role of NE stress in the development of cardiac laminopathies and unveil potential leads for its therapeutic targeting.

Key words: Cardiomyopathy, Cell biology, iPSC, nuclear mechanosensing, Microscopy, Nuclear envelope stress

Nuclear envelope stress in the development of glioblastoma multiforme
Tutor: Sarah Peeters (starting in academic year 2024-2025) - Promoter: Winnok De Vos

Glioblastoma multiforme (GBM) is one of the most lethal tumors, due to its high heterogeneity, extensive infiltration, and cell state plasticity. Recurrence is almost universal, and there is no cure, thus urging for novel research angles. GBM cells experience significant confinement owing to the high cell density and limited migration space in the brain, which alters their nuclear mechanics and might sensitize them to nuclear envelope (NE) stress. This process promotes DNA damage, which may contribute to genome instability, tumour invasion and aggressiveness. With this project, we will investigate the contribution of NE stress to the development of GBM. To this end, we will characterize the composition and fragility of the NE in a panel of patient derived GBM cells of varying aggressiveness (using qPCR, westerns and microscopy) and study the short-term and long-term effects of NE stress in a physiologically relevant 3D context (organotypic slices and organoids).

Key words: Glioblastoma, Cell biology, Nuclear envelope, DNA damage, Live cell imaging

Super-resolved analysis of clustered DNA damage repair in cancer cells
Tutor: Mirthe Vandeputte - Promoter: Winnok De Vos

Particle therapy is a promising treatment for patients with solid tumors near sensitive organs or radiation-resistant tumors. However, the induced DNA damage is complex and not well understood, precluding reliable biodosimetry in terms of individual radiation sensitivity. And while microscopy is the gold standard for gauging the level of DNA damage at the single cell level, conventional techniques fail to unravel the exact nature and composition of these clusters. With this thesis will develop expansion microscopy protocols to gain super-resolved insight in DNA damage cluster composition and to quantitatively investigate DNA damage repair kinetics after exposure to radiation. We will hereby specifically focus on the role of nuclear lamins, as they regulate nuclear architecture, DNA damage repair and mutations in their encoding genes predispose for accelerated aging disease and cancer. To do so, we will exploit a panel of genome-edited cell lines that are depleted from lamin subtypes or their critical processing enzyme. Using this highly relevant biological use-case, we expect this work to provide a quantitative insight in DNA damage and repair. This should in turn help build better predictive biophysical models that aid in clinical treatment planning based on patient’s individual radiation sensitivity.

Key words: DNA damage, Radiation, Cancer, Expansion microsopy

Cellular immunity in SARS-CoV-2 and long COVID
Tutor: Cindy Keller– Promoters: Samir Kumar-Singh, An Hotterbeekx

There is an increasing number of individuals who do not return to their baseline health after SARS-CoV-2 infection and suffer from symptoms up to 6 or even 12 months after the primary infection, a syndrome called post-acute sequalae of COVID-19 or long COVID. It has been shown that the immune system plays a major role in the development of long COVID, as inflammatory markers can remain elevated for a long period after initial infection has been cleared. In the current project we will investigate patient samples to study the early and late cellular responses for possible long-term consequences of SARS-CoV-2 infection: we will measure antibody production, seroneutralizing capacity and cytokine profiles in the serum of patients with long COVID. In addition, we will study the T- and B-cell responses in peripheral blood mononuclear cells of patients with different types of long COVID by flow cytometry. We will link these data to clinical data to gain better understanding of long COVID pathophysiology.

Key words: Mesoscale discovery, immune response, Cell culture, COVID-19, long COVID, microscopy

Ventilator-associated pneumonia and Pseudomonas aeruginosa and Staphylococcus aureus interspecies interactions
Tutor: An Hotterbeekx – Promoter: Samir Kumar-Singh

Ventilator associated pneumonia (VAP) caused by Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA) is a major contributor to high mortality and morbidity in the intensive care unit. PA is frequently resistant to multiple commonly used antibiotics, while subinhibitory concentrations of antibiotics are known to cause specific resistance-associated phenotypic effects in P. aeruginosa, which might also impact its virulence. Here the student will validate protein pathways involved in biofilm formation and virulence, which were identified earlier to be differentially expressed under antibiotic pressure. To do so, the student will perform bacterial cultures under antibiotic pressure, measure biofilm formation and interspecies competition, perform RNA extraction and quantitative PCR and will investigate structural changes using microscopy. Furthermore, the student will investigate bacterial interspecies interactions between P. aeruginosa and S. aureus, and their effect on bacterial virulence.

Key words: Pneumonia, Pseudomonas aeruginosa, virulence factors, biofilm, antibiotic resistance

Hyperthermia as a potential therapy in pancreatic ductal adenocarcinoma treatment
Tutor: Robin Colenbier - Promoters: John-Paul Bogers and Jean-Pierre Timmermans

Pancreatic ductal adenocarcinoma (PDAC) is the cancer type with the worst prognosis and very high resistance to conventional chemotherapeutic drugs. As a result, patients are in need for novel and efficacious treatments. Initial in vitro and in vivo experiments on the effect of moderate hyperthermia (up to 41.5 °C) have demonstrated synergism between hyperthermal treatment and routinely used chemotherapeutic drugs for PDAC. Nevertheless, most in vitro evaluations have been performed on 2D monocultures. These models do not closely resemble the complex tumour environment, limiting the translational value of these results into clinical practise. During this project, the student will exploit our recently optimised chorio-allantoic membrane xenograft model to investigate several combinations of whole-body hyperthermia treatment (WBHT) with chemotherapeutic drugs in this chicken embryo-based in vivo/in ovo model. The aim is to discover a safe treatment protocol with improved anti-tumour efficacy, potentially allowing dose-reduction of the chemotherapeutic drugs. Aside from routine cell culture techniques, the student will be offered an active role in the planning and execution of the in ovo experiments, including (immuno-)histological analysis of the xenografted tumours and chick organs of interest. As the CAM model is relatively little used in the investigation of solid tumours, further optimisation and novel techniques are also being investigated.

Key words: pancreatic cancer, therapy resistance, whole-body hyperthermia, chorio-allantoic membrane model, tumour histology