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,SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9,SOX17,PDX1,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,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 ∼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 3-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 immuno-compromised 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.

New insights into pancreatic cancer stem cells

“…Lgr5 also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) or Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is the Wnt target gene that marks Wnt driven actively dividing stem cells [41][42][43] . In the stem cell hierarchy, LGR5 is on a higher level than CD133, however, its expression and function in the tissues of pancreatic cancer is unclear.…”

Recent Advances in the Concept and Pathogenesis of IgG4-Related Disease in the Hepato-Bilio-Pancreatic System

“…Among the involved organs in IgG4-RD, recent studies suggest an extremely high association of pancreatic and biliary lesions 5,20,21. As both peribiliary glands in the biliary tract and pancreatic duct glands associated with pancreatic ducts in human are intermingled with small amounts of pancreatic exocrine acini,57 and the biliary tree-derived stem cells may be involved in a pancreatic organogenesis in mice 58. Nakanuma et al 59.…”

Cell sources for regenerative medicine of the liver and endoderm organs: strategies and perspectives

“…Organoids containing Lgr5+ cells were able to be expanded ex vivo and to give rise to hepatocytes and cholangiocytes (16). Long-term expansion of adult bile duct-derived bipotent progenitor cells has been obtained from human liver (17,18). A key feature of the expanded cells is the high stability at the chromosome and structural level and the single base changes occur at very low rates (16).…”