Ductular Reaction Cells Display an Inflammatory Profile and Recruit Neutrophils in Alcoholic Hepatitis

作者：Beatriz Aguilar‐Bravo, Daniel Rodrigo‐Torres, Sílvia Ariño, Mar Coll, Elisa Pose, Delia Blaya, Isabel Graupera, Luis Perea-Unceta, Júlia Vallverdú, Teresa Rubio‐Tomás, Laurent Dubuquoy, Carolina Armengol, Antonio Lo Nigro, Peter Stärkel, Philippe Mathurin, Ramon A. Bataller, Joan Caballería, Juan José Lozano, Pere Ginès, Pau Sancho‐Bru · 发表于：Hepatology · 年份：2018 · DOI：10.1002/hep.30472 · 被引用次数：92 · 研究领域：Liver Disease Diagnosis and Treatment、Alcohol Consumption and Health Effects、Diabetes and associated disorders

Chronic liver diseases are characterized by the expansion of ductular reaction (DR) cells and the expression of liver progenitor cell (LPC) markers. In alcoholic hepatitis (AH), the degree of DR expansion correlates with disease progression and short‐term survival. However, little is known about the biological properties of DR cells, their impact on the pathogenesis of human liver disease, and their contribution to tissue repair. In this study, we have evaluated the transcriptomic profile of DR cells by laser capture microdissection in patients with AH and assessed its association with disease progression. The transcriptome analysis of cytokeratin 7‐positive (KRT7+) DR cells uncovered intrinsic gene pathways expressed in DR and genes associated with alcoholic liver disease progression. Importantly, DR presented a proinflammatory profile with expression of neutrophil recruiting C‐X‐C motif chemokine ligand (CXC) and C‐C motif chemokine ligand chemokines. Moreover, LPC markers correlated with liver expression and circulating levels of inflammatory mediators such as CXCL5. Histologically, DR was associated with neutrophil infiltration at the periportal area. In order to model the DR and to assess its functional role, we generated LPC organoids derived from patients with cirrhosis. Liver organoids mimicked the transcriptomic and proinflammatory profile of DR cells. Conditioned medium from organoids induced neutrophil migration and enhanced cytokine expression in neutrophils. Like...