Lymphatic Dysplasia Shapes Liver Epithelial Outcomes in Biliary Atresia
Year: 2026
Type: preprint
Abstract: Biliary Atresia (BA) is the leading cause of pediatric liver transplantation. Given the heterogeneity of the disease, outcomes after diagnosis remain unpredictable. A multiscale atlas of BA hepatic tissue established early lymphatic dysplasia in infants that later proceed toward liver failure and transplantation (‘severe BA’). An architecturally distorted, immature and CCL21 high lymphatic vasculature marked severe BA, along with an expanding cholangiocyte compartment pivoting toward immune-reactive MMP7/SOX9 high states. Hepatocyte-to-biliary trans differentiation emerged broadly across all BA– and non-BA-cholestatic injuries, while dedifferentiation and acute-phase-reactions were specific to severe BA. Functionally, lymphatic endothelial tissue, isolated from severe BA livers, induced an analogous LGR5- and SOX9 -positive epithelial progenitor response when assembled with cholangiocytes as organoids. Further experiments revealed that lymphatic endothelium signals ectopically on liver epithelium via CCL21-CCR7-axis after BA-specific inflammatory priming. CCL21-depletion strategies mitigated the BA-specific MMP7-program. In sum, a maladaptive lymphatic endothelial dysplasia perturbs intrahepatic epithelium in severe BA and offers CCL21 as a possible target for epithelial stability.
Source: medRxiv
Authors: Leonie Schumm, Robert Lorenz Chua, Matylda Zofia Kuzinska, Mijuna Meindl, Susanna Quach, Julian Weihs, Dominic Gogol, Marius Zschiesche, Reinhild Duennebacke, Marie Uecker, Rose Behncke, Alexander Sudy, Johannes Liebig, Jan-Christopher Kamp, Martin Kucklick, Brigitta Globke, Robert Öllinger, Joachim Kübler, Stephan Henning, Christoph Slavetinsky, René Hägerling, Omid Madadi-Sanjani, Roland Eils, Adrien Guillot, Philip Bufler, Christian Conrad, Milad Rezvani
Institutions: Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité – Universitätsmedizin Berlin, Berlin-Brandenburger Centrum für Regenerative Therapien, Medizinische Hochschule Hannover, Helmholtz Centre for Infection Research, Technische Universität Braunschweig, Vienna General Hospital, Medical University of Vienna, Klinikum Bremen-Mitte, University Children's Hospital Tübingen, University of Tübingen, University Medical Center Hamburg-Eppendorf, Shanghai Medical College of Fudan University, Heidelberg University, Fudan University, University Hospital Heidelberg, Freie Universität Berlin, Cincinnati Children's Hospital Medical Center, Technische Universität Berlin
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221653375