Lymphatic Dysplasia Shapes Liver Epithelial Outcomes in Biliary Atresia
- 1Charite Universitaetsmedizin Berlin
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 CCL21high lymphatic vasculature marked severe BA, along with an expanding cholangiocyte compartment pivoting toward immune-reactive MMP7/SOX9high 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.
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BibTeX
@misc{schumm2026lymphatic,
title = {{Lymphatic Dysplasia Shapes Liver Epithelial Outcomes in Biliary Atresia}},
author = {L. Schumm and R. L. Chua and M. Z. Kuzinska and M. Meindl and S. Quach and J. Weihs and D. Gogol and M. Zschiesche and R. Duennebacke and M. Uecker and R. Y. Behncke and A. Sudy and J. Liebig and J.-C. Kamp and M. Kucklick and B. Globke and R. Oellinger and J. Kuebler and S. Henning and C. Slavetinsky and R. Haegerling and O. Madadi-Sanjani and R. Eils and A. Guillot and P. Bufler and C. Conrad and M. Rezvani},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.26365253},
url = {https://www.medrxiv.org/content/10.64898/2026.10.12.26365253v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Lymphatic Dysplasia Shapes Liver Epithelial Outcomes in Biliary Atresia
AU - L. Schumm
AU - R. L. Chua
AU - M. Z. Kuzinska
AU - M. Meindl
AU - S. Quach
AU - J. Weihs
AU - D. Gogol
AU - M. Zschiesche
AU - R. Duennebacke
AU - M. Uecker
AU - R. Y. Behncke
AU - A. Sudy
AU - J. Liebig
AU - J.-C. Kamp
AU - M. Kucklick
AU - B. Globke
AU - R. Oellinger
AU - J. Kuebler
AU - S. Henning
AU - C. Slavetinsky
AU - R. Haegerling
AU - O. Madadi-Sanjani
AU - R. Eils
AU - A. Guillot
AU - P. Bufler
AU - C. Conrad
AU - M. Rezvani
PY - 2026
DA - 2026/10/12
PB - medRxiv
DO - 10.64898/2026.10.12.26365253
UR - https://www.medrxiv.org/content/10.64898/2026.10.12.26365253v1
AB - 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 CCL21high lymphatic vasculature marked severe BA, along with an expanding cholangiocyte compartment pivoting toward immune-reactive MMP7/SOX9high 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.
ER -