Biliary tree stem cells, precursors to pancreatic committed progenitors: Evidence for possible life-long pancreatic organogenesis

Yunfang Wang, Giacomo Lanzoni, Guido Carpino, Cai Bin Cui, Juan Dominguez-Bendala, Eliane Wauthier, Vincenzo Cardinale, Tsunekazu Oikawa, Antonello Pileggi, David Gerber, Mark E. Furth, Domenico Alvaro, Eugenio Gaudio, Luca Inverardi, Lola M. Reid

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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. Stem Cells 2013;31:1966-1979

Original languageEnglish (US)
Pages (from-to)1966-1979
Number of pages14
JournalSTEM CELLS
Volume31
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • biliary tree stem cells
  • maturational lineages
  • organogenesis
  • pancreas
  • pancreatic duct glands
  • peribiliary glands

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

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