Modelling CADASIL with patient iPSC-based 3D vessel-on-chip

Awardee: Saskia Lesnik-Oberstein

Institution: Leiden University Medical Center

Grant Amount: $60,228

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

CADASIL is an hereditary small vessel disease caused by mutations in the NOTCH3 gene. These mutations lead to progressive changes in small brain arteries and reduced blood flow to the brain. Patients with CADASIL suffer from strokes and vascular dementia from mid-adulthood. It has recently been shown by our research group, that some NOTCH3 mutations lead to a much earlier onset of CADASIL than other mutations, but why this is the case is not yet understood. CADASIL vessel models representing both severe and mild mutations will enable us to study the molecular mechanisms underlying these differences and will teach us about CADASIL disease pathomechanisms in general. Our university medical center is a CADASIL expert center and for this project we will collaborate with the internationally leading vessel model group in our research center. Together, we will develop 3D CADASIL vessels-on-chip, built up of CADASIL vascular cells. These cells are obtained by harvesting pluripotent stem cells from blood samples of CADASIL patients with different mutations. The stem cells are then differentiated into vascular cells and incorporated into the chips. We will examine structural and functional abnormalities of the vessel wall and the differences between vessels with severe and mild mutations. We aim to share these CADASIL vessel-on-chip with the international CADASIL research community to promote CADASIL research.