Single-cell RNA sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation.
CFLD
complement
inflammation
non‐cirrhotic portal hypertension
porto‐sinusoidal vascular disorders
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
07 Jun 2024
07 Jun 2024
Historique:
revised:
04
04
2024
received:
27
11
2023
accepted:
21
04
2024
medline:
7
6
2024
pubmed:
7
6
2024
entrez:
7
6
2024
Statut:
aheadofprint
Résumé
Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD). Since endothelial cells (ECs) are an important component in PSVD, we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA-seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues. We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs-coined CF LSECs-upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs. Our work showed novel aspects of human liver ECs at the single-cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases.
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD).
METHODS
METHODS
Since endothelial cells (ECs) are an important component in PSVD, we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA-seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues.
RESULTS
RESULTS
We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs-coined CF LSECs-upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs.
CONCLUSIONS
CONCLUSIONS
Our work showed novel aspects of human liver ECs at the single-cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : King Baudouin Foundation
Organisme : Mucovereniging
Organisme : UZ Leuven
Organisme : I-SITE NExT Junior Talent
Organisme : European Regional Development Fund (FEDER)
Organisme : Vaincre La Mucoviscidose and Grégory Lemarchal Associations
ID : RF20220503033
Organisme : Methusalem funding (Flemish government)
Organisme : Research Foundation Flanders (FWO-Vlaanderen)
Organisme : ERC Proof of Concept
Organisme : ERC Advanced Research
Organisme : Fonds Wetenschappelijk Onderzoek-Vlaanderen
ID : 18B4322N
Informations de copyright
© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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