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Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non\u2010cirrhotic portal hypertension, recently classified as porto\u2010sinusoidal vascular disorders (PSVD).<\/jats:p><\/jats:sec>Methods<\/jats:title>Since endothelial cells (ECs) are an important component in PSVD, we performed single\u2010cell RNA sequencing (scRNA\u2010seq) 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\u2010seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex\u00a0vivo on patient tissues.<\/jats:p><\/jats:sec>Results<\/jats:title>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\u2014coined CF LSECs\u2014upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our work showed novel aspects of human liver ECs at the single\u2010cell 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15963","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T09:07:46Z","timestamp":1717751266000},"page":"2382-2395","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Single\u2010cell RNA<\/scp> sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation"],"prefix":"10.1111","volume":"44","author":[{"given":"Mathias","family":"Declercq","sequence":"first","affiliation":[{"name":"Department of Development and Regeneration, Woman and Child Unit KU Leuven Leuven Belgium"},{"name":"Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology VIB Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0735-9000","authenticated-orcid":false,"given":"Lucas","family":"Treps","sequence":"additional","affiliation":[{"name":"Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology VIB Leuven Belgium"},{"name":"Nantes Universit\u00e9, INSERM UMR 1307, CNRS UMR 6075, Universit\u00e9 d'Angers, CRCI2NA Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Geldhof","sequence":"additional","affiliation":[{"name":"Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology VIB Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4241-0396","authenticated-orcid":false,"given":"Nadine V.","family":"Conchinha","sequence":"additional","affiliation":[{"name":"Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology VIB Leuven Belgium"},{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina Universidade de Lisboa Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura P. 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