Glands of bile and pancreatic ducts as a niche of biliary stem cells and pancreatic committed progenitors

Abstract

Peribiliary glands (PBGs) in bile duct walls (Carpino et al., 2012), and pancreatic duct glands (PDGs) associated with pancreatic ducts contain a continuous, ramifying network of cells in overlapping maturational lineages (Wang et al., 2013). Our aims have been to investigate the presence of stem/progenitor cells within glands associated with bile and pancreatic ducts. Our results showed that proximal (PBGs)-todistal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG, OCT4, and SOX2) and proliferation (PCNA), 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). Biliary tree-derived cells behaved as stem cells in culture under expansion conditions, proliferating for months as undifferentiated cells; on the other hand, pancreas-derived cells underwent only approximately 8-10 divisions, then partially differentiated towards an islet fate. Both could be driven for an islet fate (HDM-P), to form spheroids with ultrastructural, electrophysiological and functional characteristics of neo-islets, including glucose regulatability. Implantation of these neo-islets into epididymal fat pads of immunocompromised diabetic mice was able to alleviate hyperglycemia by the secretion of glucose-regulated human C-peptide.