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2013 - CTS 2013 Congress


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Oral Communications 8

16.4 - Peribiliary glands stem cells and pancreatic duct glands committed progenitors: stemness, beta cell differentiation potential and cell-surface markers for prospective isolation

Presenter: Giacomo, Lanzoni, Miami, United States
Authors: Giacomo Lanzoni1,2,3,4,5,6, Yunfang Wang1,2,3,4,5,6, Eliane Wauthier1,2,3,4,5,6, Cai-Bin Cui1,2,3,4,5,6, Tsunekazu Oikawa1,2,3,4,5,6, Guido Carpino1,2,3,4,5,6, Vincenzo Cardinale1,2,3,4,5,6, Domenico Alvaro1,2,3,4,5,6, Eugenio Gaudio1,2,3,4,5,6, Mark Furth1,2,3,4,5,6, Juan Domínguez-Bendala1,2,3,4,5,6, Lola Reid1,2,3,4,5,6, Luca Inverardi1,2,3,4,5,6

Peribiliary glands stem cells and pancreatic duct glands committed progenitors: stemness, beta cell differentiation potential and cell-surface markers for prospective isolation

Giacomo Lanzoni1,2,3,4,5,6, Yunfang Wang1,2,3,4,5,6, Eliane Wauthier1,2,3,4,5,6, Cai-Bin Cui1,2,3,4,5,6, Tsunekazu Oikawa1,2,3,4,5,6, Guido Carpino1,2,3,4,5,6, Vincenzo Cardinale1,2,3,4,5,6, Domenico Alvaro1,2,3,4,5,6, Eugenio Gaudio1,2,3,4,5,6, Mark Furth1,2,3,4,5,6, Juan Domínguez-Bendala1,2,3,4,5,6, Lola Reid1,2,3,4,5,6, Luca Inverardi1,2,3,4,5,6

1Diabetes Research Institute, University of Miami, Miami, FL, United States; 2Department of Cell and Molecular Physiology and Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC, United States; 3Department of Health Science, University of Rome "Foro Italico", Rome, Italy; 4Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza", Rome, Italy; 5Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, University of Rome “La Sapienza”, Rome, Italy; 6Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston Salem, NC, United States

 

The existence and the phenotypic traits of stem/progenitor cells in the postnatal pancreas are actively debated. This is hindering investigations aimed at determining whether such populations might be involved in pathological processes in type 1 and type 2 diabetes. Moreover, ways to isolate stem/progenitor cells from cadaveric donors or surgical resections could pave new paths for regenerative strategies for diabetes. We investigated the presence of cells with stemness signatures in the pancreas and biliary tree of cadaveric donors. We performed in situ immunofluorescence for markers of pluripotency, proliferation, early and late pancreatic commitment, and endocrine maturation. We isolated cell cultures under conditions designed for stem cells: Kubota Medium (KM) and plastic adherence. We assessed the in vitro differentiation potential of the isolated cells in a serum-free hormonally defined medium (HDM-P) and extracellular matrix components tailored for an islet fate. We tested the in vivo differentiation potential into immunocompromised Rag-/-/Ilrg2r-/- mice chemically rendered diabetic with streptozotocin. The most primitive stem cell populations were found in peribiliary glands of the hepato-pancreatic common duct: these cells express biomarkers for both liver and pancreas, including markers of pluripotency, endodermal lineage, and early hepatic and pancreatic commitment (NANOG+, OCT4+, SOX2+/-, SALL4+, SOX17+, PDX1+, SOX9+ and NKX6-1+ subpopulations, NGN3-). Populations with signatures of committed progenitors (SOX17-, PDX1+, NGN3+ and SOX9+ subpopulations) were present in PDGs. Populations at different stages of development were discriminated by combinations of the surface markers EpCAM, SSEA4 and Syndecan-1. Cell cultures were isolated in KM and differentiated to a mature fate in HDM-P. The cells matured into glucose-regulatable, insulin-producing cells both in culture and after transplantation in vivo. The net findings were that peribiliary glands (PBG) of the biliary tree bear stem cells of endodermal nature and pancreatic duct glands (PDG) harbor pancreatic progenitors. Cells are organized in proximal-to-distal maturational lineages: PBG cells near the duodenum express at high levels markers of pluripotency and early hepato-pancreatic commitment; committed progenitors in PDGs display a loss of pluripotency and hepatic markers and increased expression of pancreatic endocrine maturational markers. Biliary tree stem cells may precur committed progenitors within the pancreas and islet cells.
PBG cells can be instructed to lineage restrict to a specific adult fate under defined culture conditions or if transplanted in vivo.  Combinantions of the cell-surface markers EpCAM, SSEA4 and Syndecan-1 can be used to distinguish the lineage stage and represent a novel tool for the immunoselection of stem and progenitor cells for the beta cell fate. 


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