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The extrahepatopancreatic ducts as a novel source of hepatic progenitors

肝胰外管作为肝祖细胞的新来源

基本信息

批准号：
10242937
负责人：
P. Duc Si Dong
金额：
$ 42.9万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242937
关键词：
Adopted Alagille Syndrome Attention Automobile Driving Bile fluid Biliary Candidate Disease Gene Cells Characteristics Complex Development Disease Duct (organ) structure Ductal Epithelial Cell Duodenum Endoderm Fibroblast Growth Factor Gallbladder Gap Junctions Genes Genetic Genetic Models Genetic Techniques Hepatic Hepatocyte Homeostasis Human Imaging Techniques Intestines Lead Ligands Light Liver Liver Regeneration Liver diseases Mammals Mesenchymal Microscopy Modeling Multipotent Stem Cells Mus Natural regeneration Organ Organoids Pancreas Pancreatic enzyme Pattern Phenocopy Primitive foregut structure Process Proliferating Research Research Proposals Role SOX17 gene Signal Transduction Source Structure System Testing Tissue Model Tissues Tubular formation Undifferentiated Villus Zebrafish cell motility cholangiocyte crypt cell intestinal crypt intrahepatic liver development liver injury migration notch protein novel progenitor regeneration model regenerative regenerative biology regenerative cell response single-cell RNA sequencing stem cell population stem cells transdifferentiation

项目摘要

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.

项目总结