Organoid technology holds great promise for regenerative medicine but has not
yet been applied to humans. We address this challenge using cholangiocyte
organoids in the context of cholangiopathies, which represent a key reason for
liver transplantation. Using single-cell RNA sequencing, we show that primary
human cholangiocytes display transcriptional diversity that is lost in organoid
culture. However, cholangiocyte organoids remain plastic and resume their in vivo
signatures when transplanted back in the biliary tree. We then utilize a model of
cell engraftment in human livers undergoing ex vivo normothermic perfusion to
demonstrate that this property allows extrahepatic organoids to repair human
intrahepatic ducts after transplantation. Our results provide proof of principle
that cholangiocyte organoids can be used to repair human biliary
epithelium.
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