title: Peribiliary Glands as a Niche of Extrapancreatic Precursors Yielding Insulin-Producing Cells in Experimental and Human Diabetes.
abstract: Peribiliary glands (PBGs) are niches in the biliary tree and containing heterogeneous endodermal stem/progenitors cells that can differentiate, in vitro and in vivo, toward pancreatic islets. The aim of this study was to evaluate, in experimental and human diabetes, proliferation of cells in PBGs and differentiation of the biliary tree stem/progenitor cells (BTSCs) toward insulin-producing cells. Diabetes was generated in mice by intraperitoneal injection of a single dose of 200 mg/kg (N = 12) or 120 mg/kg (N = 12) of streptozotocin. Liver, pancreas, and extrahepatic biliary trees were en bloc dissected and examined. Cells in PBGs proliferated in experimental diabetes, and their proliferation was greatest in the PBGs of the hepatopancreatic ampulla, and inversely correlated with the pancreatic islet area. In rodents, the cell proliferation in PBGs was characterized by the expansion of Sox9-positive stem/progenitor cells that gave rise to insulin-producing cells. Insulin-producing cells were located mostly in PBGs in the portion of the biliary tree closest to the duodenum, and their appearance was associated with upregulation of MafA and Gli1 gene expression. In patients with type 2 diabetes, PBGs at the level of the hepatopancreatic ampulla contained cells showing signs of proliferation and pancreatic fate commitment. In vitro, high glucose concentrations induced the differentiation of human BTSCs cultures toward pancreatic beta cell fates. The cells in PBGs respond to diabetes with proliferation and differentiation towards insulin-producing cells indicating that PBG niches may rescue pancreatic islet impairment in diabetes. These findings offer important implications for the pathophysiology and complications of this disease. Stem Cells 2016;34:1332-1342.
authors: Department of Movement, Human and Health Sciences, University of Rome "Foro Italico,", Rome, Italy.
authors: Guido
authors: G
authors: Carpino
authors: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
authors: Rosa
authors: R
authors: Puca
authors: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
authors: Vincenzo
authors: V
authors: Cardinale
authors: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
authors: Anastasia
authors: A
authors: Renzi
authors: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
authors: Gaia
authors: G
authors: Scafetta
authors: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
authors: Lorenzo
authors: L
authors: Nevi
authors: Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy.
authors: Massimo
authors: M
authors: Rossi
authors: Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy.
authors: Pasquale B
authors: PB
authors: Berloco
authors: Department of Clinical Medicine, Gastroenterology Division, Sapienza University of Rome, Rome, Italy.
authors: Stefano
authors: S
authors: Ginanni Corradini
authors: Department of Cell and Molecular Physiology, Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors: Lola M
authors: LM
authors: Reid
authors: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
authors: Marella
authors: M
authors: Maroder
authors: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
authors: Eugenio
authors: E
authors: Gaudio
authors: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.|Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy.
authors: Domenico
authors: D
authors: Alvaro
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000166:cytology*; D002451:Cell Compartmentation; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D008810:Mice, Inbred C57BL; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology*; D013311:Streptozocin
chemical_list: D007328:Insulin; D013311:Streptozocin; D005947:Glucose
keywords: Biliary tree; Endoderm; Peribiliary gland; Regeneration; Stem cell; Streptozotocin