{"doi":"10.1016/j.jhepr.2025.101617","title":"3D endothelial cell scaffolds protect liver explants and exhibit therapeutic effects on liver fibrosis","abstract":"Background & Aims Endothelial cells (ECs) display myriad protective roles that support tissue homeostasis. Embedding healthy ECs in 3D scaffolds stabilizes their phenotype to maximize reparative effects and shields immunogenicity. Here, we evaluate the protective effects of matrix-embedded ECs (MEECs) in liver explants and models of chronic liver disease. Methods Precision cut liver slices (PCLS) from patients with cirrhosis (n = 8) and fibrotic or healthy mice (n = 6) were co-cultured with MEECs for 24 h and hepatic viability and inflammation were analyzed. The protective effects of the MEECs secretome were explored in vitro . MEECs were perihepatically or subcutaneously implanted for 1 week in fibrotic mice with or without hepatectomy (n = 6) to evaluate their effects on liver inflammation, regeneration, and fibrosis. Results MEECs protected liver viability in PCLS from patients with cirrhosis (ATP/protein, 2.7 vs. 5.0, p = 0.01) and fibrotic (5.3 vs. 7.1, p = 0.01) or healthy (7.8 vs. 10.6, p = 0.01) mice, and reduced injury-induced inflammation. MEECs produced hepatocyte growth factor and fibroblast growth factor 2, which were associated with improved hepatic viability and anti-inflammatory macrophage polarization, respectively. Perihepatic implantation of MEECs in fibrotic mice with or without hepatectomy reduced inflammation and hepatic damage and exhibited pro-regenerative and antifibrotic properties (Sirius red + area, 8.3 vs. 6.4, p = 0.005). These antifibrotic effects were associated with higher production of heparan sulfate and metalloproteinases 2 and 9, and mitigation of hepatic stellate cell activation. Implantation of MEECs at a distance from the liver did not reduce liver injury, inflammation, or fibrosis. Conclusions Endothelial–hepatocyte regulation is essential in liver repair, and matrix-embedded endothelial cells (MEECs) appear to be a potential therapy for chronic liver injury and ex situ preservation of liver grafts. Impact and implications Organ transplantation is the most effective therapy for advanced liver disease, yet remains limited by preservation of harvested graft viability and injury-induced inflammation post implantation. Healthy ECs display myriad protective roles that contribute to tissue homeostasis. In this study, we show how MEECs preserve cell viability and reduce inflammation in hepatic explants and display anti-inflammatory, antifibrotic and pro-regenerative properties in the liver of fibrotic mice. These dynamic and unique hepatoprotective properties of MEECs highlight their potential therapeutic utility for chronic liver injury or ex situ conservation of liver grafts.","journal":"JHEP Reports","year":2025,"id":576900,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1291727,"name":"Alazne Moreno-Lanceta","orcid":"0000-0002-7317-7419","position":1,"is_corresponding":false},{"id":1485703,"name":"Blanca Simón-Codina","orcid":"0000-0002-3965-4170","position":2,"is_corresponding":false},{"id":1485704,"name":"David Saavedra-Pérez","orcid":"0000-0002-9705-5328","position":3,"is_corresponding":false},{"id":1061850,"name":"Yiliam Fundora","orcid":"0000-0003-4950-6988","position":4,"is_corresponding":false},{"id":1485705,"name":"Francisco Jesús González Sánchez","orcid":"0000-0002-7736-8001","position":5,"is_corresponding":false},{"id":1485706,"name":"Meritxell Perramón","orcid":"0000-0002-1944-8337","position":6,"is_corresponding":false},{"id":1485707,"name":"Laura Macías‐Muñoz","orcid":"0000-0002-8314-3087","position":7,"is_corresponding":false},{"id":774028,"name":"Manuel Morales‐Ruiz","orcid":"0000-0002-9074-2272","position":8,"is_corresponding":false},{"id":12687,"name":"Elazer R. Edelman","orcid":"0000-0002-7832-7156","position":9,"is_corresponding":false},{"id":774027,"name":"Wladimiro Jiménez","orcid":"0000-0002-9376-0214","position":10,"is_corresponding":false},{"id":1130632,"name":"Pedro Melgar‐Lesmes","orcid":null,"position":11,"is_corresponding":false},{"id":1485702,"name":"Mireia Medrano-Bosch","orcid":"0000-0001-6588-8053","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:58:00.620755Z","pmid":"41674897","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}