A Microphysiological HHT-on-a-Chip Platform Recapitulates Patient Vascular Lesions

Area of Science:

• Vascular Biology
• Rare Disease Research
• Biomedical Engineering

Background:

• Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disorder causing fragile vascular malformations (VMs).
• Current understanding of HHT pathogenesis, particularly the role of ACVRL1 mutations, remains incomplete.
• Limited treatment options exist for HHT patients.

Purpose of the Study:

• To develop a human cell-based microphysiological model of HHT.
• To investigate the biological mechanisms underlying HHT-related vascular malformations (VMs).
• To identify potential therapeutic targets for HHT.

Main Methods:

• Development of a Vascularized Micro-organ (VMO) platform for HHT modeling (HHT-VMO).
• Utilized inducible ACVRL1-knockdown in primary human endothelial cells (EC) to control Alk1 expression.
• Employed single-cell RNA sequencing and chimera experiments to analyze lesion formation.

Main Results:

• The HHT-VMO model successfully recapitulated patient-specific VMs.
• Evidence suggests cell non-autonomous effects and microvessel pruning in AVM formation.
• VEGFR inhibitor pazopanib blocked lesion formation, aligning with clinical observations.

Conclusions:

• The novel HHT-on-a-chip model provides a faithful platform for studying HHT disease.
• The model facilitates deeper understanding of HHT pathophysiology, including the roles of Alk1 and PDGFB.
• This platform can accelerate the discovery and testing of new HHT therapeutics.