Project Summary
While foregut endoderm research has primarily focused on the development and regeneration of the liver,
pancreas, and intestine, relatively little attention have been placed on the nexus by which these organs are
connected. The mammals and zebrafish the extrahepatopancreatic duct (EHPD) system functions as a tubular
network joining the liver, pancreas, and gall bladder together with the duodenum. Extensive genetic and
morphogenetic conservation between human and zebrafish EHPDs not only qualifies the zebrafish as a practical
genetic model for this tissue, but also suggests more critical roles for the EHPDs beyond simply transporting
hepatic bile and pancreatic enzymes. We propose here to leverage the zebrafish vertebrate model to rigorously
explore the function of EHPD cells as a novel and significant source of progenitors for liver development,
homeostasis, and regeneration.
Using a zebrafish model that phenocopies hepatic biliary cell loss in Alagille Syndrome (ALGS), we found
that agenesis of intrahepatic duct (IHD) cells, due to transient loss of the Notch ligand Jagged, can lead to a
robust cellular response outside the liver, within the EHPD. Specifically, the EHPD cells react to the liver duct
cell loss by proliferating excessively and contributing primarily to the regenerated IHD cells and hepatocytes
also. These unexpected findings suggest that the EHPD system harbors multipotent progenitors that can
contribute to the liver. Our discovery of multipotent progenitors residing in the EHPD leads to fundamental new
questions: To what extent and by what mechanisms do the EHPD cells contribute to the liver during development,
homeostasis, and regeneration? And how are these progenitors formed and maintained?
We hypothesize that the EHPDs act as the initial source of nearly all progenitors for the liver. We posit
that EHDP progenitors have high proliferative capacity and are maintained in an undifferentiated, quiescent state
by FGF signaling. Further, we hypothesize that these EHPD cells are poised for expansion and migration to
become distributed throughout the liver, ultimately adopting cholangiocyte or hepatocyte identity during
development and homeostasis, and to a greater degree, in response to specific types of liver damage. Insufficient
EHPD progenitors may lead to alternative mechanisms of regeneration such as transdifferentiation. Testing
these hypotheses may lead to a unifying, dynamic liver regeneration model, whereby the availability of EHPDs
progenitors is a significant determinant of which regenerative mechanism predominates.
Uncovering a more fundamental role for the EHPD cells in liver regenerative biology will advance our
understanding and treatment of liver diseases including ALGS and other cholangiopathies, as well as hepatocyte
disorders. A central role for the EHPD in liver regeneration would also implicate it as a novel target tissue for
liver therapies. We propose to investigate the lineage contribution of EHPD cells during liver development,
homeostasis, and regeneration, and the genetic and cellular mechanisms driving this complex process.