Study identifies cell signals that might be intercepted to treat PLD

Following on from our recent article on polycystic liver disease (PLD), we’re excited to share some new research in this field. Researchers in Edinburgh, the Netherlands, Italy and Spain have discovered cell signals that could possibly be intercepted to stop liver cysts growing in PLD.

The main genes involved in ADPKD – PKD1 and PKD2 – make proteins called polycystin 1 and polycystin 2. These proteins are found on hair-like structures called cilia on cells lining tubes in the kidney and liver. Researcher Dr Scott Waddell from the MRC Human Genetics Unit in Edinburgh likens the cilia to antennae because they can pick up and relay signals from other cells.  

Polycystin 1 and 2 interfere with the cilia, causing liver cysts to form. But how? Scott and the team designed research to find out.  

They used genetic engineering to stop the cilia working in the livers of mice, mirroring what happens in ADPKD. Without functioning cilia, the cells in the mouse livers switched to a new way of signalling, using a protein called TGFβ. This caused them to make extracellular matrix, which acts as scaffolding for new cells being constructed.  

The researchers thought the liver cysts were using this matrix to grow. To prove this, they intercepted the TGFβ signals using an inhibitor. Guess what — the matrix was not made, and the cysts stopped growing! The researchers discovered that the same TGFβ signals occur in liver cells from people with ADPKD. When they inhibited TGFβ signalling, the cyst cells stopped growing in the lab. 

The team also found that cyst cells make a protein called integrin which helps them to detect the extracellular matrix. When they blocked integrin with an inhibitor, this also stopped cyst growth! 

So, the researchers think that TGFβ inhibitors and integrin inhibitors could be potential treatments for PLD.  

Dr Luke Boulter enthused, “Advancing treatment for patients with often neglected genetic diseases requires team science. We were delighted to work with scientists, geneticists and clinicians across Europe to unpick the biology of polycystic disease with the hope of developing new medicines for patients living with this disease.”  

TGFβ inhibitors and integrin inhibitors are already being used, or tested, for some other conditions. They’ll need to be researched further and carefully tested in clinical trials before they could become available as a treatment for PLD.  

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