On June 26th Dennis Nahon successfully defended his thesis, entitled ‘Modeling vascular disease using self-assembling human induced pluripotent stem cell derivatives in 3D Vessels-on-Chip’ at Leiden University. His research was performed under the supervision of Christine Mummery and Valeria Orlova at LUMC
Vascular diseases are a significant burden due to inadequate treatment options, partly because current preclinical models, like mice or cultured cells, fail to replicate human physiology accurately. Organ-on-Chip (OoC) technology offers a solution by realistically mimicking organ functions in microscopic culture environments. HiPSCs), which can differentiate into nearly all cell types, are particularly promising for disease modeling and drug development.
In his thesis Dennis Nahon explored the development of Vessels-on-Chip (VoC) models using human induced pluripotent stem cells (hiPSCs) to study neurovascular disorders. HiPSC lines were generated, and disease-causing mutations were corrected using CRISPR-Cas9 for several conditions, such as cerebral amyloid angiopathy (CAA), RVCL-S, and Hereditary Hemorrhagic Telangiectasia 1 (HHT1).
For RVCL-S, ‘healthy’ (corrected) and ‘diseased’ hiPSC-derived endothelial cells (ECs) were characterized by 2D assays, but no differences were observed, indicating the need for more complex models to detect disease phenotypes.
For HHT1, initial 2D assays using ‘healthy’ and ‘diseased’ hiPSC-derived ECs did not show differences. However, differences were identified after integrating the cells into a more complex VoC model. The ECs, together with supporting pericytes, formed a complex 3D microvascular network in microfluidic chips. The ‘healthy’ ECs formed larger and more stable blood vessels with more direct interactions with pericytes than the ‘diseased’ ECs. This lack of stability and interaction aligns with patient data, highlighting the value of such complex VoC models.
Additionally, efforts were made to advance the current VoC model into a brain-specific blood-brain barrier (BBB) model. HiPSC-derived astrocytes were successfully integrated into the VoC model, showing direct interactions between the cells that resemble those observed in the human body. It was also demonstrated that mimicking blood flow or adding specific components in the chip can enhance the development of these astrocyte-containing VoC models.
The work in this thesis demonstrates the potential of using stem cells and VoC models for complex disease modeling. Future work will continue to refine existing models and investigate disease mechanisms in greater detail.
