Characterization of Patient-Derived GNAQ Mutated Endothelial Cells from Capillary Malformations

Capillary malformations (CM) (port-wine stains) are congenital skin lesions that are characterized by dilated capillaries and postcapillary venules. CMs are caused by altered functioning of the vascular endothelium. Somatic genetic mutations have predominantly been identified in the endothelial cell...

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Veröffentlicht in:Journal of investigative dermatology 2024-06, Vol.144 (6), p.1378-1388.e1
Hauptverfasser: Langbroek, Ginger Beau, Stor, Merel L E, Janssen, Vera, de Haan, Annett, Horbach, Sophie E R, Graupera, Mariona, van Noesel, Carel J M, van der Horst, Chantal M A M, Wolkerstorfer, Albert, Huveneers, Stephan
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container_end_page 1388.e1
container_issue 6
container_start_page 1378
container_title Journal of investigative dermatology
container_volume 144
creator Langbroek, Ginger Beau
Stor, Merel L E
Janssen, Vera
de Haan, Annett
Horbach, Sophie E R
Graupera, Mariona
van Noesel, Carel J M
van der Horst, Chantal M A M
Wolkerstorfer, Albert
Huveneers, Stephan
description Capillary malformations (CM) (port-wine stains) are congenital skin lesions that are characterized by dilated capillaries and postcapillary venules. CMs are caused by altered functioning of the vascular endothelium. Somatic genetic mutations have predominantly been identified in the endothelial cells of CMs, providing an opportunity for the development of targeted therapies. However, there is currently limited in-depth mechanistic insight into the pathophysiology and a lack of preclinical research approaches. In a monocenter exploratory study of 17 adult patients with CMs, we found somatic sequence variants in the GNAQ (p.R183Q, p.R183G, or p.Q209R) or GNA11 (p.R183C) genes. We applied an endothelial-selective cell isolation protocol to culture primary endothelial cells from skin biopsies from these patients. We successfully expanded patient-derived cells in culture in 3 of the 17 cases while maintaining endothelial specificity as demonstrated by vascular endothelial-cadherin immunostainings. In addition, we tested the angiogenic capacity of endothelial cells from a patient with a GNAQ (p.R183G) sequence substitution. These proof-of-principle results reveal that primary cells isolated from CMs may represent a functional research model to investigate the role of endothelial somatic mutations in the etiology of CMs, but improved isolation and culture methodologies are urgently needed to advance the field.
doi_str_mv 10.1016/j.jid.2023.10.033
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CMs are caused by altered functioning of the vascular endothelium. Somatic genetic mutations have predominantly been identified in the endothelial cells of CMs, providing an opportunity for the development of targeted therapies. However, there is currently limited in-depth mechanistic insight into the pathophysiology and a lack of preclinical research approaches. In a monocenter exploratory study of 17 adult patients with CMs, we found somatic sequence variants in the GNAQ (p.R183Q, p.R183G, or p.Q209R) or GNA11 (p.R183C) genes. We applied an endothelial-selective cell isolation protocol to culture primary endothelial cells from skin biopsies from these patients. We successfully expanded patient-derived cells in culture in 3 of the 17 cases while maintaining endothelial specificity as demonstrated by vascular endothelial-cadherin immunostainings. In addition, we tested the angiogenic capacity of endothelial cells from a patient with a GNAQ (p.R183G) sequence substitution. 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subjects Adult
Biopsy
Capillaries - abnormalities
Capillaries - pathology
Cells, Cultured
Endothelial Cells - metabolism
Female
GTP-Binding Protein alpha Subunits - genetics
GTP-Binding Protein alpha Subunits, Gq-G11 - genetics
GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
Humans
Male
Middle Aged
Mutation
Port-Wine Stain - genetics
Port-Wine Stain - pathology
Skin - blood supply
Skin - cytology
Skin - pathology
Vascular Malformations - genetics
Vascular Malformations - pathology
Young Adult
title Characterization of Patient-Derived GNAQ Mutated Endothelial Cells from Capillary Malformations
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