Moderator of 1 Session
Presenter of 1 Presentation
DEVELOPING IPSC-DERIVED HUMAN BRAIN TISSUE MODELS OF NEURODEGENERATIVE DISEASES
Abstract
Aims
Brain research heavily depends on models recapitulating key aspects of human brain physiology and disease pathology. Human iPSCs have great potential to complement existing disease models, as they allow directly studying affected human cell types. In addition, recent developments in CRISPR genome editing revolutionized how impacts of genetic alterations on disease formation can be investigated. Co-culture of disease-relevant iPSC-derived cells with disease-relevant mutations enables studying complex phenotypes involving cellular crosstalk.
Methods
Combining these technologies we established a new generation of iPSC-based human brain tissue models for neurodegenerative and neurovascular brain diseases. We successfully established a multicellular brain tissue model containing iPSC-derived cortical neurons, astrocytes, microglia, and recently also oligodendrocytes.
Results
Our technology provides highly controllable and reproducible 3-dimensional tissues with typical cell morphologies and functional features, including complex somatodendritic morphology of neurons, widespread synapse formation, spontaneous and induced electrical activity, network formation, microglial ramification and tiling etc. Tissues can be cultured for over 12 months in a postmitotic state without signs of proliferation or cell death, thus providing a more controllable, reproducible, and long-lived alternative to cortical organoids currently used for 3D disease modelling. To establish human models of AD, FTD-Tau, or neurovascular diseases, we used our efficient CRISPR pipeline to introduce synergistic disease-associated mutations to accelerate naturally occurring disease processes and promote pathology. We will present a first phenotypic characterization of our multicellular tissue models.
Conclusions
We expect that these models will support studies elucidating novel, potentially human-specific pathomechanisms and provide a human framework for translation and screening.