Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets

Abstract

Multipotent stem/progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato-pancreatic common duct, cystic duct, and hilum. They express endodermal transcription factors (e.g., Sox9, SOX17, FOXA2, PDX1, HES1, NGN3, PROX1) intranuclearly, stem/progenitor surface markers (EpCAM, NCAM, CD133, CXCR4), and sometimes weakly adult liver, bile duct, and pancreatic genes (albumin, cystic fibrosis transmembrane conductance regulator [CFTR], and insulin). They clonogenically expand on plastic and in serum-free medium, tailored for endodermal progenitors, remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ≈36 hours and slowing to one every 2-3 days. Transfer into distinct culture conditions, each comprised of a specific mix of hormones and matrix components, yields either cords of hepatocytes (express albumin, CYP3A4, and transferrin), branching ducts of cholangiocytes (expressing anion exchanger-2-AE2 and CFTR), or regulatable C-peptide secreting neoislet-like clusters (expressing glucagon, insulin) and accompanied by changes in gene expression correlating with the adult fate. Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes, whereas if into fat pads of streptozocin-induced diabetic mice, results in functional islets secreting glucose-regulatable human C-peptide. Conclusion: The phenotypes and availability from all age donors suggest that these stem/progenitors have considerable potential for regenerative therapies of liver, bile duct, and pancreatic diseases including diabetes. (HEPATOLOGY2011;) © 2011 American Association for the Study of Liver Diseases

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…Pre-clinical studies have reinforced this thought process, where immunohistochemical studies from BC samples revealed phenotypic traits of cholangiocytes and progenitor cells consistent with their anatomic sites of origin, confirming the heterogeneity between the three groups (2). Progenitor cells from the canals of Hering have been identified in IHCC, while those within the peribiliary glands have been identified in EHCC and gallbladder cancers, respectively (2)(3)(4)(5). Furthermore, the increased availability of next-generation sequencing panels has facilitated this thought process by allowing us to understand the tumor somatic variants and genomic heterogeneity between the three groups.…”

Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes

“…23 Sox9 is an endodermal transcription factor, and EpCAM is a stem/progenitor cell surface marker. [24][25][26] Immunostaining showed that CK19 and OV6 were expressed in proliferated cholangiocytes after BDL treatment (Figures 2a and b). Co-immunostaining revealed that OV6/CK19, Sox9/CK19 were extensively co-expressed in proliferated cholangiocytes (Figures 2c and d) and immunoblotting confirmed CK19, OV6, Sox9, and EpCAM protein gradually increased (Figure 2e).…”

Pathomorphological analysis of nonalcohoholic and alcoholic steathohepatitis adverse consequences

“…Известно, что активированные овальные прогениторные клетки, локализованные в нишах канальцев Геринга, при делении дают потомст-во 2-х фенотипически разных линий клеток пе-чени, одна из которых дифференцируется в ге-патоциты, а вторая -в холангиоциты [24]. В дифференциации прогениторных клеток печени активную роль выполняют Notch-сигналы и Wnt-белки: при билиарной дифференцировке экспрессия Jagged 1 миофибробластами усили-вает Notch-сигнализацию в прогениторных клетках и их дифференцировку в холангиоциты; при снижении Notch сигналов и активации сек-реции Wnt3a макрофагами прогениторные клет-ки параллельно дифференцируются в гепатоци-ты [25].…”