Jag1Ndr/Ndr mice, a model that recapitulates hallmark features of Alagille syndrome (ALGS), mimic various aspects of liver disease observed in patients, according to a study conducted by researchers in Sweden and Belgium.

The study was recently presented as poster at the European Association for the Study of the Liver (EASL) 2023 Congress in Vienna, Austria.

All Jag1Ndr/Ndr pups displayed strong cholestasis at birth. By postnatal day 30, when mice were sacrificed, the researchers identified 3 distinct phenotypic groups:

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  • Mild phenotype (15 of 47 mice), presenting with bile ducts and clear plasma. This group resembled patients with recovered bile ducts
  • Intermediate severity phenotype (21 of 47 mice), showing ongoing regeneration and bile infarcts
  • Regeneration-incompetent mice (11 of 47 mice), displaying severe jaundice and large bile infarcts. This group resembled patients requiring liver transplantation

Read more about ALGS etiology

The regenerating livers exhibited bile infarcts comprising 3% to 10% of the liver surface (preliminary data), infiltrated by cells expressing alpha-smooth muscle actin (aSMA), a myofibroblast marker, and lined by hepatocytes expressing the transcription factor SOX9. These findings suggest ongoing biliary reprogramming in these regions.

Conversely, severe Jag1Ndr/Ndr mice predominantly displayed aSMA-negative bile infarcts, which occupied up to 16% of the liver surface. Moreover, the presence of SOX9-positive hepatocytes around the bile infarcts was less dense and scattered.

“We hypothesize that aSMA+ bile infarcts act as signaling centers for hepatocyte conversion and biliary regrowth. Using spatial transcriptomics, we are investigating the molecular landscape of the bile infarct microenvironment,” the authors said.

The results also showed that intermediate severity mice had a robust proliferative response, as demonstrated by the increase in cells expressing the proliferation marker Ki67, whereas severe mice did not.

Currently, the researchers are analyzing spatial transcriptomic sequencing data of bile infarcts from regenerating and severe livers.

Reference

Sevenants L, Verhulst S, Hildebrandt F, Ankarklev J, van Grunsven L, Van Hul NKM, Andersson E. Phenotypic diversity and regeneration in a model of Alagille syndrome recapitulate patient heterogeneity. Presented at: European Association for the Study of the Liver (EASL) 2023 Congress, Vienna, Austria; June 21-24, 2023.

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