Intrahepatic duct cells regenerate upon resumption of Jagged/Notch signaling, a study using a zebrafish model of Alagille syndrome found.
Based on this finding, the authors of the study postulated that if Jagged/Notch signaling is increased, using Notch agonists or gene therapy, for example, the regeneration of intrahepatic duct cells may be enhanced. This could be a potential therapeutic approach in patients with Alagille syndrome, in whom intrahepatic duct cells are lost, leading to cholestasis.
Cholestasis can resolve in some patients with the disease, suggesting that the intrahepatic duct cells regenerate to some extent. However, the exact mechanism of how this occurs remains unknown.
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Here, a team of researchers led by Duc Dong, PhD, used a zebrafish model to elucidate the mechanisms driving intrahepatic duct cell regeneration following Jagged loss. They showed that leveraging the transience of Jagged knockdown in juvenile zebrafish resumed Jagged expression and led to robust intrahepatic duct cell regeneration.
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The researchers also discovered that the primary source of progenitor cells that contributed to this regeneration was the extrahepatic duct. They showed that these progenitors proliferate and migrate into the liver when Notch signaling is lost. On the other hand, when Notch signaling increases, they differentiate into intrahepatic duct cells.
Using a dominant-negative fibroblast growth factor (FGF) receptor approach, the researchers also showed that FGF signaling likely plays a role in this process. More precisely, they found that FGF signaling from the surrounding mesenchymal cells maintains this extrahepatic niche. The researchers suggested that it does this directly by preventing the premature differentiation and allocation of extrahepatic duct progenitors to the liver.
The authors added, “Indeed, transcriptional profiling and functional analysis of adult mouse [extrahepatic duct] organoids uncover their distinct differentiation and proliferative potential relative to [intrahepatic duct] organoids.”
Alagille syndrome is thought to affect around 1 in 70,000 newborns. However, this figure is based on the diagnosis of liver disease in infants and may be an underestimate. There is currently no cure for the disease.
Reference
Zhao C, Lancman JJ, Yang Y, et al. Intrahepatic cholangiocyte regeneration from an Fgf-dependent extrahepatic progenitor niche in a zebrafish model of Alagille syndrome. Hepatology. Published online September 27, 2021. doi:10.1002/hep.32173
