The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: A new reference frame for disease and regeneration

Abstract

Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self-replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. Conclusion: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. (HEPATOLOGY 2016;64:277-286)

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

“…However, the peripheral IHBD and EHBD/large IHBD are embryologically different and thus may exhibit distinct properties other than IL-33 signaling. PBGs have attracted attention as a BEC stem-cell niche and a potential origin of ECC (10). In the present study, IHC analysis of E-cadherin and lineage-tracing of LacZ-labeled cells suggests that ECC can originate from cells in the PBGs.…”

Cell sources for regenerative medicine of the liver and endoderm organs: strategies and perspectives

“…On the other hand, determined stem/progenitor cell population resides into the adult and fetal human liver; in adults, hepatic stem/progenitor cells (HpSCs) are located within the canals of Hering and bile ductules; HpSCs are facultative stem cells characterized by an unique phenotype and able to differentiate into functional mature hepatocytes and cholangiocytes (14). In fetal liver, HpSCs form the ductal plate and give rise to the generation of cholangiocytes of interlobular bile ducts and to periportal hepatocytes during liver development (14).…”

“…In fetal liver, HpSCs form the ductal plate and give rise to the generation of cholangiocytes of interlobular bile ducts and to periportal hepatocytes during liver development (14). HpSCs can be easily isolate from human livers on the basis of the expression of specific surface antigens such as Epithelial Cell Adhesion Molecule (EpCAM) (15).…”

“…HpSCs can be easily isolate from human livers on the basis of the expression of specific surface antigens such as Epithelial Cell Adhesion Molecule (EpCAM) (15). Moreover, a single Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive liver stem cell can be expanded to form epithelial spheroids in vitro and was able to differentiate into functional hepatocytes in vitro and in vivo (14,16). Organoids containing Lgr5+ cells were able to be expanded ex vivo and to give rise to hepatocytes and cholangiocytes (16).…”

“…Extrahepatic biliary tree contains a large population of progenitor/stem cells named biliary tree stem/progenitor cells (BTSCs) (17). From an anatomical point of view, BTSCs reside within peribiliary glands (17); embryological, they represent the remnant in the adult organs of the common biliopancreatic progenitors derived from the ventral endoderm of primitive duodenum (14). BTSCs can be easily isolated from adult or fetal organs, rapidly and clonal expand in culture and can differentiate toward several endoderm cell types including hepatocytes, cholangiocytes and pancreatic endocrine cells (17,24).…”