New genetic drivers in hemorrhagic hereditary telangiectasia

Cerdà, Pau; Castillo, Sandra D.; Aguilera, Cinthia; Iriarte, Adriana; Rocamora, José Luis; Larrinaga, Ane M.; Viñals, Francesc; Graupera, Mariona; Riera-Mestre, Antoni

doi:10.1016/j.ejim.2023.08.024

Cited by 4 publications

(1 citation statement)

References 64 publications

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“…Although many mutated genes in HHT encode components of the TGF-β signaling pathway ( e . g ., ENG, ALK1, SMAD4, and GDF2), a recent study identified other genes (INHA, HIFA, DNM2, POSTN, and ANGPTL4) as potential drivers of HHT [ 44 ]. Dysregulation of EC responsiveness to hypoxia as a result of mutations in these genes, together with environmental hypoxia, may contribute to vascular abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Employment of diverse in vitro systems for analyzing multiple aspects of disease, hereditary hemorrhagic telangiectasia (HHT)

Koh,

Kang,

Mao

et al. 2024

Cell Biosci

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Background In vitro disease modeling enables translational research by providing insight into disease pathophysiology and molecular mechanisms, leading to the development of novel therapeutics. Nevertheless, in vitro systems have limitations for recapitulating the complexity of tissues, and a single model system is insufficient to gain a comprehensive understanding of a disease. Results Here we explored the potential of using several models in combination to provide mechanistic insight into hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder. Genome editing was performed to establish hPSCs (H9) with ENG haploinsufficiency and several in vitro models were used to recapitulate the functional aspects of the cells that constitute blood vessels. In a 2D culture system, endothelial cells showed early senescence, reduced viability, and heightened susceptibility to apoptotic insults, and smooth muscle cells (SMCs) exhibited similar behavior to their wild-type counterparts. Features of HHT were evident in 3D blood-vessel organoid systems, including thickening of capillary structures, decreased interaction between ECs and surrounding SMCs, and reduced cell viability. Features of ENG haploinsufficiency were observed in arterial and venous EC subtypes, with arterial ECs showing significant impairments. Molecular biological approaches confirmed the significant downregulation of Notch signaling in HHT-ECs. Conclusions Overall, we demonstrated refined research strategies to enhance our comprehension of HHT, providing valuable insights for pathogenic analysis and the exploration of innovative therapeutic interventions. Additionally, these results underscore the importance of employing diverse in vitro systems to assess multiple aspects of disease, which is challenging using a single in vitro system.

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Section: Discussionmentioning

confidence: 99%