Researchers found a way to ease intrahepatic bile duct paucity in Alagille syndrome (ALGS) that involves correcting the defective peribiliary mesenchyme. The results of the study will be presented at The Liver Meeting® this November.

“Further refining the subpopulations of cells comprising the peribiliary mesenchymal niche for intrahepatic bile duct development, homeostasis, and repair will potentially identify biomarkers, genetic modifiers, and/or novel therapeutic targets for ALGS and other hepatobiliary liver diseases,” the researchers wrote in the abstract.

The analysis of transcriptomic data showed that hepatocytes of Jagged1 haploinsufficient mice were able to partially enter the transcriptional program of cholangiocytes but could not complete it with success. According to the authors, this might result from a defect in the peribiliary mesenchymal cell niche that compromises intrahepatic bile duct development and/or reprogramming. This hypothesis needs further investigation.


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In addition, the reestablishment of Jagged1 expression in the peribiliary mesenchyme of Jagged1 haploinsufficient mice rescued bile duct paucity. The same was not observed upon re-expression of Jagged1 in the hepatic epithelium.

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The researchers used single-cell transcriptomics and Resolve spatial transcriptomic platforms to assess cell states and spatial association in liver samples obtained from mice with Jagged1 haploinsufficiency and patients with ALGS.

Previous studies from the same authors have demonstrated that hepatocyte-to-cholangiocyte reprogramming could originate in the intrahepatic bile duct system that failed to form during development, thereby resolving cholestasis and reversing fibrosis. The hepatocyte-derived biliary system developed even in the absence of functional Notch signaling. However, the process of hepatocyte-to-cholangiocyte reprogramming is impaired in most patients with ALGS.

Reference

Huppert KA, Rendeiro AF, Cast AE, et al. Using mouse genetics, single cell and spatial transcriptomics to reveal the defects in Alagille syndrome hepatocyte to cholangiocyte reprogramming. Hepatology. 2022;76(S1):S1559-S1560.