Impact of Gallbladder Hypoplasia on Hilar Hepatic Ducts in Biliary Atresia

This study is a collaborative effort between the veterinary anatomist (Nanae) and the pediatric surgeon (Shohei). We and our collaborators have been studying biliary atresia in mice for over ten years in the department of veterinary anatomy and treating human biliary atresia for over forty years in the department of pediatric surgery. This research is super exciting because it brings together veterinary and medical sciences in a new way.

So, what’s the deal with biliary atresia? It’s a serious liver disease in newborns where the bile ducts, which transport bile, get damaged. SOX17 is really important for forming the gallbladder (part of the bile duct system that stores bile). Mice with mutations in Sox17 show a small gallbladder and fetal biliary atresia. In humans, some cases have shown low SOX17 expression in the gallbladder, but the exact causes and mechanisms behind biliary atresia are still not fully understood. In veterinary medicine, biliary atresia has been seen in animals with gallbladders, like over 200 newborn sheep and cattle, as well as dogs, monkeys, and cats. Their condition is very similar to human biliary atresia. Interestingly, horses, which don’t have a gallbladder, rarely get this disease. This suggests that having a gallbladder during fetal development might be linked to biliary atresia.
Using a new technique, Nanae injected dye into the abdomens of fetal mice to study how bile flows (or doesn’t flow) in Sox17 heterozygous mutant mice. In Sox17+/- fetuses with severe liver damage, bile flow was significantly reduced, causing it to stagnate in the liver. Unlike normal mice, Sox17+/- fetuses had a bile duct that split into multiple thin ducts in the hepatic hilum, much like human biliary atresia. These fetuses also had cells from the bile ducts inside the liver that had migrated to the bile ducts outside the liver, and the bile duct network was reduced, leading to bile stasis and early liver fibrosis. Shohei thought that abnormal gallbladder development might be contributing to human biliary atresia. When we looked at human cases, we found that reduced SOX17 expression was linked to smaller gallbladders and liver damage. We saw similar results in Sox17 mutant mice.
Our findings suggest that when the gallbladder doesn’t develop properly, it causes the bile duct in the hepatic hilum to branch out too much and the bile ducts inside the liver to protrude. This abnormal development extends to the bile ducts inside the liver lobule. We believe that the results of this study offer hope to many children suffering from this condition.
The comment from Nanae: Developing the fetal cholangiography technique and selecting a suitable contrast agent were very difficult tasks, but through a combination of effort and a series of coincidences, we were able to obtain beautiful cholangiograms. I would like to express my deep gratitude to Professor Kanai for his advice.
The comment from Shohei: Through collaborative research with a veterinary anatomist, I learned new approaches to diseases from a comparative anatomical perspective. I am grateful to Professor Kanai for his guidance. I also thank my family (Etsuko, Kentaro, Hana) for their support during this time.

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