These authors contributed equally to the study.
Article first published online: 30 NOV 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 6, pages 2159–2172, December 2011
How to Cite
Cardinale, V., Wang, Y., Carpino, G., Cui, C.-B., Gatto, M., Rossi, M., Bartolomeo Berloco, P., Cantafora, A., Wauthier, E., Furth, M. E., Inverardi, L., Dominguez-Bendala, J., Ricordi, C., Gerber, D., Gaudio, E., Alvaro, D. and Reid, L. (2011), Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology, 54: 2159–2172. doi: 10.1002/hep.24590
Potential conflict of interest: Dr. Reid consults, received grants from, and holds intellectuals property rights for Vesta and GigaCyte. She also received grants from and holds intellectual property rights for Vertex.
Support: (UNC) Funding derived from a grant from the North Carolina Biotechnology Center (NCBC), GigaCyte Biotech (Branford, CT), Vesta Therapeutics (Bethesda, MD), and from NIH grants (AA014243, IP30-DK065933), NIDDK Grant (DK34987), and an NCI grant (CA016086); (Sapienza University) Dr. Cardinale received salary support from a scholarship from Sapienza University of Rome for the studies that he did at UNC. D. Alvaro and V. Cardinale were supported by FIRB grant no. RBAP10Z7FS_004; D. Alvaro, V. Cardinale, E. Gaudio, and G. Carpino were supported by a grant from Agenzia Regionale Del Lazio Per I Trapianti E Le Patologie Connesse; E. Gaudio was supported by MIUR grants: PRIN#2007, prot. 2007HPT7BA_001 and Federate Athenaeum funds from the University Sapienza of Rome; (Diabetes Research Institute) The studies were funded by grants from NIH, the Juvenile Diabetes Research Foundation, ADA, and the Diabetes Research Institute Foundation.
Patent: A patent on the biliary tree stem cells was filed in November, 2009 and is jointly owned by UNC in Chapel Hill, NC, and Sapienza University in Rome, Italy.
- Issue published online: 30 NOV 2011
- Article first published online: 30 NOV 2011
- Accepted manuscript online: 1 AUG 2011 08:19AM EST
- Manuscript Accepted: 20 JUL 2011
- Manuscript Revised: 14 JUL 2011
- Manuscript Received: 14 MAY 2011
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;)