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Chavarria Vilarasau, LaiaAutor o CoautorAguilar-Bravo BAutor o CoautorAriño SAutor o CoautorBlaya DAutor o CoautorPose EAutor o CoautorMartínez García De La Torre RaAutor o CoautorMartinez-Sanchez CAutor o CoautorZanatto LAutor o CoautorSererols-Viñas LAutor o CoautorCantallops-Vilà PAutor o CoautorAffo SAutor o CoautorColl MAutor o CoautorBataller RAutor o CoautorGines PAutor o CoautorSancho-Bru PAutor (correspondencia)

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Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming

Publicado en:Journal Of Hepatology. 79 (3): 728-740 - 2023-09-01 79(3), DOI: 10.1016/j.jhep.2023.04.013

Autores: Aguilar-Bravo, Beatriz; Arino, Silvia; Blaya, Delia; Pose, Elisa; de la Torre, Raquel A Martinez Garcia; Latasa, Maria U; Martinez-Sanchez, Celia; Zanatto, Laura; Sererols-Vinas, Laura; Cantallops-Vila, Paula; Affo, Silvia; Coll, Mar; Thillen, Xavier; Dubuquoy, Laurent; Avila, Matias A; Argemi, Josepmaria; Paz, Arantza Lamas; Nevzorova, Yulia A; Cubero, Francisco Javier; Bataller, Ramon; Lozano, Juan Jose; Gines, Pere; Mathurin, Philippe; Sancho-Bru, Pau

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Background & Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood. Methods: HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. Results: Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients’ outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. Conclusions: This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. Impact and implications: Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair. © 2023 European Association for the Study of the Liver

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