A new study conducted by researchers from the Karolinska Institute in Sweden, and Genentech in the United States, has provided valuable evidence for molecular diversity in Alagille syndrome (ALGS) biliary cells and highlighted the potential therapeutic role of insulin-like growth factor 1 (IGF1) in rescuing biliary growth and survival.

“Patients with ALGS display peripheral intrahepatic bile duct paucity. Intriguingly, some patients and the Jag1Ndr/Ndr mouse model for ALGS can de novo generate their biliary system,” the researchers explained.

According to the results recently presented at the European Association for the Study of the Liver (EASL) Congress, intrahepatic cholangiocyte organoids (ICOs) derived from hilar and peripheral regions of adult Jag1+/+ and Jag1Ndr/Ndr mouse livers are functionally and molecularly distinct from each other and from corresponding Jag1+/+ ICOs.

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Notably, Jag1Ndr/Ndr hICOs showed significant growth impairment compared with Jag1+/+ hICOs and Jag1Ndr/Ndr pICOs. Moreover, both Jag1Ndr/Ndr hICOs and pICOs showed decreased proliferation compared with Jag1+/+ ICOs.

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Bulk RNA sequencing analysis of regional ICOs confirmed the downregulation of cell cycle-associated genes in Jag1Ndr/Ndr ICOs, providing additional support for the observed decreased proliferation.

The study also demonstrated that treatment with IGF1 specifically rescued survival and growth of Jag1Ndr/Ndr pICOs, but not hICOs. These findings suggest that IGF1 holds promise as a potential therapeutic target for ALGS.

Furthermore, RNA sequencing analysis revealed that Jag1Ndr/Ndr hICOs expressed a hepatocyte-like signature with activated IGF1 signaling pathway components, whereas Jag2 and Nrarp, which are Notch components, were downregulated.

Previously, the researchers had already shown that de novo generation of the ALGS biliary system occurred through distinct architectural mechanisms in the hilum and periphery.

Reference

Iqbal A, Van Hul NKM, Belicova L, Corbat A, Hankeova S, Andersson E. IGF1 specifically rescues peripheral intrahepatic biliary organoids from a mouse model of Alagille syndrome. Poster presented at: the European Association for the Study of the Liver (EASL) Congress, Vienna, Austria; June 21-24, 2023.

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