High importance
Aug 13, 2026
To develop a microphysiological system (HHT-on-a-chip) that mimics vascular lesions observed in patients with Hereditary Hemorrhagic Telangiectasia (HHT) to enhance understanding of the disease mechanisms and potential treatments.
Creation of a perfused vasculature model using primary endothelial cells (EC) with inducible shRNA targeting endogenous Alk1 to study the development of vascular malformations (VM). Single-cell transcriptomics was employed to analyze cellular changes and identify potential therapeutic targets.
The HHT-on-a-chip model successfully reproduced the appearance of vascular malformations seen in HHT patients, demonstrating that a subpopulation of Alk1-deficient EC can initiate VM development. The study found that microvessel pruning and regression play a role in VM formation, and that inhibition of VEGF/VEGFR pathways can block these lesions.
The model may not fully replicate all complexities of HHT pathology, as it is based on a simplified in vitro system. Additionally, long-term effects and interactions with other cellular and molecular pathways may not be fully captured.
This research provides a valuable tool for studying HHT by recreating patient-specific vascular lesions in a controlled setting. It is crucial for identifying new therapeutic approaches and understanding the underlying mechanisms of HHT, which can lead to improved management and treatment options for patients.
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations (VM) focally develop in multiple organs. There are few treatment options and no cure. HHT patients inherit loss-of-function mutations affecting Alk1-Eng signaling; however, why this manifests as VMs remains poorly understood. Here we have developed a fully human cell-based microphysiological system of perfused vasculature in which inducible shRNA controls endogenous Alk1 in primary endothelial cells (EC). Resulting VMs develop over several days, recapitulate patient VM appearance, and require only a subpopulation of Alk1-deficient EC to trigger lesions. Single-cell transcriptomics suggests microvessel pruning and regression contribute to VM, while loss of PDGFB implicates mural cell recruitment. Finally, pharmacological VEGF/VEGFR inhibition blocks lesion formation. In summary, we have developed an HHT-on-a-chip model that faithfully reproduces HHT patient lesions and that can be used to better understand HHT disease biology and identify potential new HHT drugs.