Novel cellular models to study cholangiopathies

A major problem in cholangiocyte research is the lack of in vitro human models to study the pathogenesis of cholangiopathies and to validate potential therapeutic targets. Our current knowledge of the field derives mainly from studies using in vivo animal models or in vitro primary cell culture systems and immortalized cell lines. While the use of rodent models suffers often from a lack of phenotype reproducibility, primary human cholangiocytes are difficult to isolate, de-differentiate after a few passages, and in very short supply. Furthermore, immortalized cell lines do not faithfully recapitulate normal physiological functions of cholangiocytes.

Availability of reliable human in-vitro models would facilitate the understanding of the pathophysiology of these elusive diseases. Taking advantage of the latest advances in stem cell technology, our lab has available two in vitro models of human cholangiocytes, one derived from induced-pluripotent stem cells (iPSCs) and the second from adult primary isol

greatest advantage of iPSCs is that they can be derived from biopsy samples (i.e skin, blood) and they maintain a very high replicative potential that provides an unlimited source of patient-specific cells able to differentiate into the somatic cell of interest. On the other hand, the organoids are well differentiated and, as compared to iPSCs, have a long-term genetic stability in culture.

Our lab has established a protocol for the generation of human polarized cholangiocytes from patients using iPSC and we are developing novel 3D liver organoid based platforms that will be useful to address more complex aspects of the interactions of biliary cells with other cells or with pathogens in biliary diseases. As part of the program of the Yale Liver Center we are also actively banking blood cells for the generation of iPSC and liver organoids from explant liver tissue of patients enrolled at the YLC registry.