Abstract / Summary
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 transdifferentiation emerged broadly across 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.