Current PhD/Postdoc Projects
Alba Herrero Alonso
|"The role of never healing wounds in malignancy, CAFs in liver tumors"
Chronic liver disease results in fibrosis, thereby creating a suitable environment in which primary liver tumours develop. Furthermore, the liver is an important site for metastasis of other tumours such as colon, breast, lung, and melanoma cancer. In both cases, patients have a poor prognosis and liver cancer is associated with high mortality. Most anti- liver cancer treatments focus on the rapidly dividing and evolving cancer cells, unfortunately unsuccessfully. In this project we investigate how tumour cells communicate with cells in the tumour environment to promote their growth. The cancer associated fibroblasts, have many characteristics of liver resident stellate cells. Stellate cells are in a healthy liver involved in vitamin A storage and control the amounts of connective tissue in the organ. Upon liver injury, stellate cells activate and become scar producing myofibroblastic cells. Because of the phenotypic overlap between cancer associated fibroblasts and stellate cells, we will compare these cell types more in depth. Liver cancers show interpatient differences at different levels (genetic alterations, amount of scar, ...). Here, we will investigate the existence of cancer associated fibroblasts in different cancer backgrounds and want to know how the genetic background of the tumour can regulate its environment by activating the production of more scar by the cancer associated fibroblasts. The goal is to block the communication between tumour and cancer associated fibroblasts in order to reduce the tumour growth.
Postdoctoral fellowship from the University of the Basque Country, Spain (Dr. Alba Herrero Alonso) - 15/03/2021-14/03/2023
“CAF-cancer interactions in primary liver cancer and liver metastasis” (PhD project Elisabeth Knetemann)
Currently, the lack of representative in vitro models to study hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) are preventing CAF research from moving forward. In this project, 3D cell culture models for HCC and CRLM will be developed which can be used to find targetable interactions between CAFs and cancer cells to reduce liver tumour growth.
Team: Prof. Inge Mannaerts, Dr. Alba Alonso Herrero and MSc. Elisabeth Knetemann
Ref: Herrero, A., Knetemann, E., and Mannaerts, I. (2021). Review: Challenges of In Vitro CAF Modelling in Liver Cancers. Cancers (Basel) 13. Open access: https://www.mdpi.com/2072-6694/13/23/5914
Social Media: https://twitter.com/inge_mannaerts
This work is funded by FWO, Stichting tegen Kanker (Foundation against Cancer) and the Belgian association for study of the liver (BASL).
|"Creation of a dynamic intercellular liver communication platform to establish an anti-fibrotic combo-therapy for chronic liver diseases"
|"Development of in vitro models for advanced liver fibrosis and NAFLD"
|Liver fibrosis is caused by chronic damage to the liver leading to damage of the hepatocytes and activation of hepatic stellate cells which then produce an excessive amount of extracellular matrix proteins leading to scar tissue formation. Although many years of research around this disease, up until now no FDA approved therapies are available in the clinic. This is partly due to the lack of reliable and representative in vitro models. The aim of my PhD is to develop new in vitro models for liver fibrosis and more specifically for non-alcoholic fatty liver disease (NAFLD) to mimic these diseases in a 3D in vitro system or to use them in drug testing phase. On one hand, mouse in vitro spheroids cultures are developed by isolating primary mouse cells from a mouse liver and on the other hand spheroids are developed by using human iPSC-derived hepatic cells as a model for a human liver. These mouse and iPSC-derived liver spheroids will be optimized to reflect liver fibrosis and NAFLD in vitro.
|Mina Kazemzadeh Dastjerd
|"Development of a stem cell-derived 3D liver NAFLD culture model"
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. It can range from steatosis to a more severe state with inflammation and fibrosis. Growing evidence suggests that NAFLD is a multifactorial disease in which genetic predisposition also plays an important role, both in the aetiology and the progression of the disease. However, we lack representative models to study human NAFLD and its genetic predisposition. Therefore, the aim of this project is to develop an in vitro human NAFLD model using stem cell-derived liver cells. Stem cells expressing genetic variations that play a role in the predisposition of NAFLD are incorporated to better understand the disease genetics. The use of genetic variants in such an in vitro NAFLD model could potentially lead to the discovery of novel therapeutic approaches to treat this chronic liver disease.
This work is supported by FWO (PhD fellowship + benchfee)
|"iPSC-based parenchymal and sinusoidal liver cell mimics for DILI and NAFLD studies (iPSC-LiMic)"
|"Early mediators of hepatic stellate cell activation in liver fibrosis"
|"Multidrug testing in liver culture models"
|"Establish and characterize mouse and induced pluripotent stem cell derived liver miniorgans"
This work is funded by iBOF in collaboration with Georg Halder and Hans Oosterwyck (KULeuven)
Based on 3D cell culture technology, structure and functions in real organs are able to be partially recapitulated in miniorgans. In preliminary research, a new approach to produce liver miniorgans with higher complexity both in structure and functions through transplantation under the kidney capsule was established. In this project, we want to identify the essential cellular components required for miniorgan development and maturation and provide an approach to construct mouse and/or induced pluripotent stem cell derived liver miniorgans with high complexity. Furthermore, we want to investigate how cellular cross talk can contribute to liver miniorgan development.
|"Exploring the initiation and progression of NASH in a stem cell derived liver coculture model by revealing cellular stress activation pathways in real time"
|"Multiomics study of Liver Fibrosis Initiation"
|The main scar forming cell type in the pathological process of liver fibrosis is the hepatic stellate cell (HSC), which undergoes a myo-fibroblastic trans-differentiation process towards an activated state as a response to liver injury. An ideal anti-fibrotic therapy would target the activating or activated HSCs (aHSCs), or specific processes in these cells. Elucidation of pathways driving the activation of HSCs has led to the development of many anti-fibrotic agents currently in phase 2 or 3 clinical trials, but an effective anti-fibrotic therapy is not yet available for clinical use. In this project we will investigate the initial stages of fibrosis and stellate cell activation, that could identify the novel targets for anti-fibrosis therapy. This will be achieved by combining the two omics platforms - transcriptomics and metabolomics, of the activated stellate cells in vivo especially at the initial stages. The finding from this project could have an impact on the development of novel drugs and diagnostic markers of liver fibrosis.
|Recently Finalized PhD Projects
|Lianne Van Os
|"The role of liver sinusoidal endothelial cells in chronic liver disease"
|Liver sinusoidal endothelial cells (LSECs) are the most permeable cells of the body and very important for liver function. During chronic liver disease and fibrosis these highly specialized endothelial cells are not able to maintain their specific phenotype and lose their important characteristics. Together with our EU consortium DeLIVER we hope to unravel more about the dynamic liver sinusoidal endothelial cells in both health and disease. During my PhD project we want to establish a 3D in vitro model with hepatocytes, hepatic stellate cells and liver endothelial cells. In addition, we will look at different chronic disease models in mice to both study LSEC morphology and their role in chronic liver disease in vivo and in vitro.
|"Liver fibrosis in Organotypic Microfluidic Networks"
|One major obstacle in the development of efficient therapies for chronic liver disease, such as liver fibrosis and NAFLD, is the lack of robust and representative in vitro models, as these often fail to mimic the complex 3D structures and cellular organisation found in vivo. During my PhD project, we aim to develop biomimetic in vitro models of liver disease, which will serve to a better understanding of liver disease and will allow us to target and better understand the early initiating events and the dynamic progression of liver fibrosis leading to cirrhosis. Therefore, we make use of liver-representative microtissues, namely mouse- or human-derived organoids and precision cut liver slices, cultured in microfluidic systems, which subsequently will be used to mimic liver fibrosis/chronic liver disease, to investigate associated mechanisms and pathways.
|Vincent De Smet
|"Tackling liver fibrosis by targeting hepatic stellate cell inactivation"
|Liver fibrosis, cirrhosis and cancer are an increasing problem worldwide with a substantial global burden of disease. Liver fibrosis consists of a pathological deposition of extra-cellular matrix, which is produced by hepatic stellate cells who activate upon liver damage. When the liver injury is stopped, reversal of fibrosis is accompanied by inactivation of the HSCs. However, there is only limited knowledge on the mechanisms behind HSC inactivation. My PhD project focusses on sinusoidal cell communication to discover novel mechanisms of fibrosis development and reversal both in mice and human. Novel information gained from my PhD will fuel new treatment strategies for liver fibrosis.
|"Staging of liver fibrosis by hepatic stellate cell specific biomarkers"
In the current clinical setting, the most specific and sensitive diagnostic tool for liver fibrosis, remains the liver biopsy, an invasive procedure associated with multiple drawbacks. Although the development of multiple non-invasive means, based on serological circulating factors and/or elastographic quantifications, high diagnostic value for the identification of all stages of the liver fibrosis process is still lacking. My PhD project proposes the use of circulating extracellular vesicles, small membrane-derived structures with endocytic origin, as a novel diagnostic tool for the identification of onset and progression of liver fibrosis. As such extracellular vesicles are shed by almost all cells in the body, and have a heterogenous content consisting of proteins, small non-coding RNAs, lipids, etc, and depending on their cell-origin, we hypothesize their potential use as indicative tool for liver homeogenesis, and thus disease progression.
Finalized research projects
HILIM 3D: Humanized Immune Liver Mouse and 3D in vitro models for the study and therapy of liver disease (IWT-SBO programme 11/2014-10/2018)
Biomarkers for liver fibrosis risk assessment (FWO-V 2017)
Hepatic 3D co-culture system for the evaluation of (anti-)fibrotic compounds (IWT 2014-2017)
HEPRO II: Human liver disease: study of the hepatic stem cells and their niche, and development of novel model systems (IAP VII programme 10/2012-09/2017)
A phase I study on the feasibility and safety of mRNA immunotherapy in combination with RFA in patients with hepatocellular carcinoma (UZ Brussel W.Gepts Foundation 2013 + 2015-2016)
Liver progenitor cells, their secretome and liver regeneration (IWT 2013-2016)
Modulation of liver fibrosis by liposome-mediated selective targeting of hepatic stellate cells (IWT 2013-2016)
The link between hypoxia and progenitor cells during liver carcinogenesis (FWO-V 2013-2016)
Extensive characterization of different human liver progenitor cell populations (FWO-V 2013-2016)
Generation, Isolation and Expansion of Human Quiescent Hepatic Stellate Cells (IWT 2012-2015)
Role of ER stress in angiogenesis associated liver cirrhosis and portal hypertension (FWO-V 2012-2015)
HEMIBIO: Hepatic Microfluidic Bioreactor (EU-FP7 programme 2011-2015)
Interplay between epigenetic modification mechanisms and microRNAs (VUB GOA 2011-2015)
A 3D tissue culture model for screening of anti-fibrotic compounds (UZ Brussel W.Gepts Foundation 2015)
The Role of Autophagy in Liver Fibrosis (IWT 2011-2014)
BRUSTEM I & II: Regenerative medicine of the liver using synergistic mixtures of immature or mature human hepatocytes with mesenchymal stem / progenitor cells or with hepatic stellate cells (Brussels Government - Innoviris (impuls programme Life Sciences 06/2008-05/2011 + renewal 06/2011-05/2014))
HEPSTEM: Functional human hepatocytes, stellate cells and sinusoidal endothelial cells generated from stem cells (IWT-SBO 11/2009-10/2013)
Analysis of HDAC repressor complexes with a function during liver fibrosis (FWO-V 2009-2012)
Role of angiogenesis and angiogenetic factors (VEGF, PLGF) in portal hypertension and fibrosis formation in animal models of cirrhosis, steatosis and portal hypertension (FWO-V 2009-2012)
HEPRO: The hepatic progenitor cell niche under experimental conditions and in human liver disease (IAP VI programme 2007-2011)
Liver fibrosis as a target for non viral gene therapy (FWO-V 2009)
Biology and pathobiology of the liver progenitor cell niche (FWO-V 2008-2011)
Role of specific histon deacetylases during liver stellate cell activation and fibrogenesis (IWT 2007-2010)
Epigenetic modification of gene expression by interference with histone acetylation (VUB GOA 2006-2010)
HEPADIP: Hepatic and adipose tissue and functions in the metabolic syndrome (EU-FP6 programmme 11/2005-10/2010)
Stem cell niches in liver and pituitary : interactions between progenitors, their committed progeny, niche cells and the extracellular matrix (FWO-V equipment grant for FACSAria Cell Sorter - 2006-2009)
Role of dystrophin-associated protein complex in contraction of hepatic stellate cells (FWO-V 2006-2009)
Analysis of a transcriptional repressor complex and its function during cell type specification and differentiation (FWO-V 2008)