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

Abstract

A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner’s Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner’s Glands and in PDGs nearest the duodenum, and in humans are in Brunner’s Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors’ responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

“…In particular, we found that approximately 40% of BA cases are characterized by gallbladder wall hypoplasia with reduced SOX17 expression (i.e., SOX17-low cases) 24 . Furthermore, the ectopic presence of peribiliary glands, a feature typically associated with non-gallbladder bile duct walls and its progenitors 25 , is commonly observed in BA gallbladders, mirroring the findings in the Sox17 +/− mouse model 24 . These findings suggest possible defects in SOX17-positive gallbladder wall progenitors that are replaced by other bile duct progenitors in SOX17-low BA cases.…”

“…In this study, gallbladder hypoplasia resulting from decreased expression of SOX17 causes malformation in Sox17 haploinsufficiency mice, including the ‘cloud-like’ bile duct network and the thin branched hepatic ducts at the hepatic hilus, similar to the finding of some human BAs 42 – 44 . Taken together with the ectopic PBG (niche of stem cell in hepatic ducts 25 , 45 , 46 ) appearance in both human BA and mouse model 24 , these findings clearly imply that Sox17 heterozygous mouse model mimics the findings of human BA cases. In SOX17-low BA, gallbladder wall hypoplasia might possibly contribute to the progressive obliterative cholangiopathy by a similar mechanism in the Sox17 -mutant mouse model; however, it is impossible to prove what actually happened in the early stages that led to the scarring of the porta hepatis.…”

A gene edited pig model for studying LGR5+ stem cells: implications for future applications in tissue regeneration and biomedical research

“…We recently reported that pigs and humans have a network of co-hepato/pancreatic stem/progenitor cells in the duodenum, the peribiliary glands of the intrahepatic and extrahepatic biliary trees, and in the pancreatic duct glands of intrapancreatic biliary trees, which supports hepatic and pancreatic regeneration postnatally ( Zhang et al, 2023a ). In our adult pig model, it is possible to observe LGR5 + cells in the biliary duct ( Figure 1B ) and gallbladder ( Figures 1C,H ).…”