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. 2023 May 1;77(5):1639-1653.
doi: 10.1097/HEP.0000000000000026. Epub 2023 Jan 3.

TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia

Celia Short  1 , Allen Zhong  1 , Jiabo Xu  1 , Elaa Mahdi  1 , Alison Glazier  1 , Nicolas Malkoff  1 , Nicolas Noriega  1 , Theresa Yeo  1 , Kinji Asahina  2   3 , Kasper S Wang  1
Affiliations

TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia

Celia Short et al. Hepatology. .

Abstract

Background and aims: Biliary atresia (BA), a congenital cholestatic liver disease, commonly culminates in end-stage liver disease. We previously demonstrated in BA that Prominin-1 ( Prom1 )-expressing hepatic progenitor cells (HPCs) expand within regions of developing fibrosis, giving rise to cholangiocytes within biliary ductular reactions. Null mutation of Prom1 or ablation of cells expressing Prom1 significantly diminishes fibrogenesis. FN14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), is expressed by HPCs. TWEAK/FN14 signaling promotes fibrosis in multiple organ systems. Therefore, we hypothesized that TWEAK/FN14 signaling mediates Prom1 -expressing HPC proliferation leading to profibrogenic ductular reactions in BA.

Approach and results: The experimental mouse model of BA mediated by perinatal rhesus rotavirus (RRV) infection resulted in increased co-expression of Fn14 in Prom1 -expressing HPCs within regions of ductular reactions. FN14 antagonist L524-0366 decreased ductular reactions, biliary fibrosis and periportal fibroblast activation in RRV injury. L524-0366 inhibition also demonstrated loss of downstream noncanonical NF-kB signaling expression in RRV injury. Murine HPC organoids demonstrated accelerated organoid growth and proliferation when treated with recombinant TWEAK. Increased organoid proliferation with recombinant TWEAK was lost when also treated with L524-0366. Analysis of a large publicly available RNA sequencing database of BA and normal control patients revealed significant increases in expression of PROM1 , FN14 , and genes downstream of TNF signaling and noncanonical NF-κB signaling pathways in BA infants. Infants who failed to achieve bile drainage after hepatoportoenterostomy had higher relative levels of FN14 expression.

Conclusion: TWEAK/FN14 signaling activation in Prom1 -expressing HPCs contributes to proliferation of profibrogenic ductular reactions in BA.

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