Optimized huMan iN vItro vascularized 3D Brain tissUe model for Studying neurodegeneration

Neurodegeneration is a major health concern affecting millions of individuals in Europe, with this number constantly increasing as population ages. A cure for this spectrum of conditions is still missing, in part due to differences between available experimental models and human pathophysiology.My aim is to develop an in vitro 3D brain tissue model that combine the major brain cell types (obtained from human induced pluripotent stem cells - iPSCs) also including vascular cells, for better resembling the human brain. Currently, the available in vitro 3D brain tissue models lack a functional vasculature with brain-specific features, thus limiting the possibility to study (vascular-related) pathophysiology. Transplantation is still the only strategy leading to an extensive and functional vascularization of 3D brain models.I will combine -omics technologies for optimizing the vascularization of 3D brain tissue models. First, I will investigate whether factors released by iPSC-derived neurons and their precursor cells can promote vessel formation by the endothelium. Second, I will determine which changes occur in 3D brain tissue models upon transplantation compared with in vitro culture. I will then reproduce the identified drivers of this process for obtaining a fully in vitro vascularized 3D brain tissue model, without the need for transplantation. Finally, I will show that the manipulation of this vascularized 3D models allows for studying the vascular contribution to mechanisms of neurodegeneration and for evaluating possible intervention strategies.The optimization of in vitro vascularized 3D brain tissue models will facilitate reducing costs and number of experimental animals. Also, their ease of manipulation and high-throughput will facilitate mechanism investigation and drug screening.Altogether, the MSCA fellowship will allow me to work on a relevant project while building critical skills for continuing my career as an independent researcher.