Recent advancements in the development of models to study primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a rare non-communicable disorder that affects the liver. Chronic inflammation in and around the bile duct is followed by the development of fibrotic obstructions within the duct, causing bile to accumulate within the liver. In severe cases, patients may need a liver transplant to survive. PSC is a complex disorder, involving the liver, bile duct, and immune cell dysfunctions. Studies have also shown correlations between PSC and inflammatory bowel disorder (IBD). As a result, studying how PSC progresses and responds to potential treatments has been difficult.

A review paper published on May 5, 2026, in the journal Portal Hypertension & Cirrhosis, describes recent advancements in the development of models to study PSC. Professor Hongcui Cao of the Zhejiang University School of Medicine led this review, examining animal models, organoid models, and engineered organoids. "By elucidating the strengths and limitations of each model, a better understanding of appropriate in vitro and in vivo models will accelerate the development of therapeutic strategies for PSC," says Prof. Cao.

Mice have emerged as useful animal models of PSC and aid our understanding of the effects of excess bile retention and bile toxicity on bile duct tissue. Animal models fall into two broad categories. The first are mice that are genetically modified to increase bile acid production and retention, such as multidrug resistance-related protein 2 (Mdr2) knockout and cystic fibrosis transmembrane conductance regulator (Cftr) knockout. The second category of animal models is mice that are given drugs to induce excess bile production or chronic hepatic inflammation, such as ɑ-naphthalene isothiocyanate (ANIT) and 2,4,6-trinitrobenzene sulfonic acid (TNBS).

While these models replicate the effects of bile retention, they often do not have the intestinal symptoms that accompany PSC. The nature of tissue damage is also different. Worse, some gene knockouts can have off-target effects on other organs, which limits their utility. And some drugs have toxic effects of their own and cannot be used for long-term studies.

Understanding the molecular factors behind PSC requires human tissue, since mice have different proteins and signaling molecules. Primary hepatic cholangiocytes (PHCs), derived from the bile duct, were the earliest models used to study PSC. However, PHC cultures lack the three-dimensional structures and cell-cell interactions that are affected in PSC, which means that they did not replicate disease conditions accurately.

Organoids, or three-dimensional aggregations of cells, have addressed this gap. A variety of organoids have been developed to model different tissues affected in PSC. Organoids have been constructed from PHCs, Cholangiocyte cell lines, and induced pluripotent stem cells. These organoids have then been used to replicate liver tissue and bile duct endothelium. In addition to accurately modeling PSC, healthy organoids can be transplanted into damaged livers and heal them.

Some researchers have taken organoids a step further using bioengineering technologies. These engineered organoids have been used to build artificial bile ducts and create a so-called "liver-on-a-chip" to allow rapid analysis of drugs that treat PSC. Functional biomaterials are being developed to provide a range of mechanical and chemical support to organoids, allowing more complex organoids to be grown in-vitro.

What do these advancements mean for the future of PSC research and therapy? Prof. Cao believes that mouse models will continue to improve our understanding of the mechanical aspects of PSC. "Recent advances in organoid and bioengineered organoid technologies have provided new tools for modeling PSC, enabling studies of disease mechanisms, drug screening, and preclinical evaluation," she adds. Bioengineering will improve the stability of organoids, thus allowing them to be used more widely in both drug evaluation and tissue regeneration.

Some challenges remain, such as replicating the supply of blood vessels to these engineered structures and the effects of immune cells. However, Prof. Cao is optimistic about the future. She hopes that these advancements in both animal and organoid models will be used to address not just primary sclerosing cholangitis, but also many other rare and intractable diseases.