The Norwegian PSC Research Center (NoPSC) was established in 2008 at the Medical Department, Rikshospitalet upon signing of a contract between the University of Oslo and Rikshospitalet on the handling of funds from Canica AS. The funds are exclusively dedicated to research related to basic and clinical aspects of the chronic liver disease primary sclerosing cholangitis (PSC).

NoPSC is now a section within the Division of Surgery and Specialized Medicine at Oslo University Hospital (OUH), Rikshospitalet, and is also affiliated with the Research Institute for Internal Medicine, OUH Rikshospitalet and the Institute of Clinical Medicine at the University of Oslo.

NoPSC has a broad range of both local and international collaborators (see annual reports for more information). NoPSC established and continues to be an active part of the International PSC Study Group (www.ipscsg.org).

News

G protein-coupled receptor GPR35 is a risk gene for PSC and predisposing factor for liver and colon cancer. To study the oncogenic role of GPR35, colon cancer was assessed in normal mice (Gpr35 fl/fl) or those lacking GPR35 on a subset of immune cells called macrophages (Gpr35 delMO).

Deletion of GPR35 in macrophages significantly reduced tumor growth in two ways; first, by directly limiting the proliferation of epithelial cells and second, by affecting the ability of macrophage to create a vascularized (i.e. permessive) microenvironment.

These findings highlight a potential role for GPR35 in PSC and cholangiocarcinoma.

For more information, please click here.

Although genetic factors are thought to predispose individuals to PSC, no causative mutations have yet been identified. Now for the first time we show that a specific gene mutation in SEMA4D (encoding for the protein CD100) associates with an inherited form of PSC in a large family.

We discovered that the SEMA4D mutation causes T cell defects and mice engineered to express the mutant CD100 protein developed severe cholangitis in an experimental model of PSC. Adoptive transfer of normal T cells into the CD100-mutant mice reduced disease severity and suggests a protective role for T cells in some settings of PSC.

For more information, please see here: https://stm.sciencemag.org/content/13/582/eabb0036

Bile ducts carry bile from the liver and gall bladder to the small intestine where it aids digestion. Bile ducts are lined with important cells called cholangiocytes that modify bile as its transported through the biliary system. In PSC, the cholangiocytes and bile ducts are destroyed which impairs bile transport from the liver to the gut.

To explore if damaged bile ducts can be repaired, we expanded cholangiocytes grown in the lab from healthy human liver tissue and transferred the cholangiocytes into damaged human livers undergoing normothermic perfusion (procedure to improve liver before transplantation). We showed that cholangiocytes expanded in the lab (organoids) engrafted into the donor liver and repaired the bile duct functoin. These findings highlight a potential future treatment for PSC and patients with other bile duct diseases.

For more information, please see here: https://science.sciencemag.org/content/371/6531/839

We have previously shown that patients with PSC have alterations to the composition of their gut bacteria (microbiome) but how these changes affect liver disease is still unknown.

To address this question, we studied the genetics of the gut microbiome and found that bacteria in PSC patients have signifcantly lower numbers of genes relating to vitamin B6 and branched-chain amino acid synthesis.

Vitamin B6 and branched-chain amino acids are essential nutrients and our findings suggest that changes of the gut microbiome in PSC may influence the levels of important circulating metabolites that impact disease.

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Natural killer T (NKT) cells are abundant immune cells in liver and activated by lipids (fat molecules).

To determine if activating lipids are found in liver bile, we co-cultured NKT cell lines with bile collected from the gallbaldder of patients undergoing liver transplantation, including those with PSC.

We found that patient bile samples can activate several NKT cell lines at very low concentrations suggesting that activating lipids are present and highly potent in bile. Activating lipids in bile may originate from bacteria as one third of activating bile samples (4 of 12) contained microbial DNA.

Our results reveal lipids in bile can activate NKT cells in liver patients and these findings further support the role of NKT cells in hepatobiliary diseases such as PSC.

For more information, please visit the following link: https://onlinelibrary.wiley.com/doi/10.1111/cei.13541