title: Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis.
abstract: Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG, OCT4, and SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9, SOX17, PDX1, and LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3, MUC6, and insulin). Radial-axis lineages start in PBGs near the ducts' fibromuscular layers with stem cells and end at the ducts' lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes. Biliary tree-derived cells behaved as stem cells in culture under expansion conditions, culture plastic and serum-free Kubota's Medium, proliferating for months as undifferentiated cells, whereas pancreas-derived cells underwent only approximately 8-10 divisions, then partially differentiated towards an islet fate. Biliary tree-derived cells proved precursors of pancreas' committed progenitors. Both could be driven by three-dimensional conditions, islet-derived matrix components and a serum-free, hormonally defined medium for an islet fate (HDM-P), to form spheroids with ultrastructural, electrophysiological and functional characteristics of neoislets, including glucose regulatability. Implantation of these neoislets into epididymal fat pads of immunocompromised mice, chemically rendered diabetic, resulted in secretion of human C-peptide, regulatable by glucose, and able to alleviate hyperglycemia in hosts. The biliary tree-derived stem cells and their connections to pancreatic committed progenitors constitute a biological framework for life-long pancreatic organogenesis.
authors.affiliation: Department of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Wang
authors.forename: Giacomo
authors.initials: G
authors.lastname: Lanzoni
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.forename: Cai-Bin
authors.initials: CB
authors.lastname: Cui
authors.forename: Juan
authors.initials: J
authors.lastname: Dominguez-Bendala
authors.forename: Eliane
authors.initials: E
authors.lastname: Wauthier
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cardinale
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Oikawa
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: David
authors.initials: D
authors.lastname: Gerber
authors.forename: Mark E
authors.initials: ME
authors.lastname: Furth
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Luca
authors.initials: L
authors.lastname: Inverardi
authors.forename: Lola M
authors.initials: LM
authors.lastname: Reid
mesh_terms: D000328:Adult; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001659:Biliary Tract / Q000166:cytology*; D015415:Biomarkers / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000628:therapy; D055724:Electrophysiological Phenomena; D000071858:Epithelial Cell Adhesion Molecule; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000628:therapy; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D016381:Islets of Langerhans Transplantation; D051379:Mice; D038081:Organogenesis / Q000235:genetics; D010179:Pancreas / Q000166:cytology* / Q000254:growth & development*; D010183:Pancreatic Ducts / Q000166:cytology; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D055153:Stem Cell Niche / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule
keywords: biliary tree stem cells; maturational lineages; organogenesis; pancreas; pancreatic duct glands; peribiliary glands