Intrahepatic duct cells regenerate from multipotent progenitors that originate from stem cells just outside the liver, according to a new study published in the journal Hepatology. This finding could help researchers develop new treatments for Alagille syndrome, a disease caused by impaired Notch signaling.

“We’ve been aware of the regenerative power of the liver for a long time,” said Duc Dong, PhD, the senior author of the study in a press release from Sanford Burnham Prebys. “The stem cells that we found are actually outside the liver, not within it, which may have made their discovery difficult.”

He explained that researchers think these “outside the box” stem cells travel into the liver and multiply to repopulate the cells that are lost to the disease when there is no other option left. 


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Using a zebrafish model, Dr. Dong and his team showed that resuming the expression of Jagged1 in animals where Jagged1 expression was inhibited led to the robust regeneration of intrahepatic duct cells via a Notch-dependent mechanism. Jagged1 is the ligand of Notch.

Based on this finding, the researchers postulated that if Jagged/Notch signaling was increased via gene therapy or Notch agonists, for example, the regeneration of intrahepatic duct cells could be enhanced in Alagille syndrome patients.

“We’ve shown not just that regeneration is possible in models of Alagille syndrome, but, importantly, how it can be enhanced,” Dr. Dong said. “These missing duct cells can regenerate if Jagged/Notch is restored.” 

He added that his laboratory has developed the first potential drug that could boost the Notch signaling pathway. The team showed in another study that the potential drug could enhance regeneration and survival in animal models. They also showed that it could trigger the Notch pathway in cells obtained from patients with Alagille syndrome. Following further studies, the potential drug could be tested in clinical trials.

References

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

New stem cell identified by Sanford Burnham Prebys researchers offers hope to people with rare liver disease. News release. Sanford Burnham Prebys; October 11, 2021.