A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs versus humans

Abstract

A network of co-hepato/pancreatic stem/progenitors exists postnatally in the intrahepatic, extrahepatic and intrapancreatic biliary trees of pigs and humans and found to support hepatic and pancreatic regeneration throughout life. The stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on Correlation, hierarchical clustering, KEGG and Short Time-series Expression Miner (STEM) analyses. Representative phenotypic traits are expression of pluripotency genes (SOX2, OCT4, KLF4), endodermal transcription factors (SOX9, SOX17, PDX1, NGN3), other stem cell traits (NCAM, EpCAM, BMI-1, CD44), and proliferation biomarkers (Ki67). Stem/progenitor niches in vivo are in peribiliary glands (PBGs) throughout the intrahepatic and extrahepatic biliary tree, in duodenal submucosal glands (Brunner’s Glands), and in pancreatic duct glands (PDGs). The highest numbers of niches in humans are in PBGs in the hepato/pancreatic common duct, a duct missing in pigs; by contrast, the highest numbers in pigs are in Brunner’s Glands and in a subset of PDGS, those nearest to the duodenum. Elsewhere in PDGs in the porcine pancreas, and in all PDGs in the human pancreas, are found only committed unipotent and bipotent progenitors. Multipotentiality of the stem/progenitors was indicated by their ability to yield hepatic versus pancreatic fates under distinct ex vivo conditions or in vivo when organoids of them were transplanted onto liver versus pancreas using patch grafting strategies. The findings establish pigs as logical hosts for translational/preclinical studies assessing grafts of organoids of the biliary tree’s co-hepato/pancreatic stem cells as cell therapies for diseases and dysfunctions in liver and pancreas both for humans and for veterinary animals.