Development of next-generation 3D brain organoids for the study and modulation of immunemediated neurodegeneration in cerebrovascular disease.

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.

Keywords:NEUROINFLAMMATION, 3D CELL CULTURE, STROKE

Disciplines:Genetics, Gynaecology and obstetrics, Molecular and cell biology, Morphological sciences