Polycystic kidney disease recreated from stem cells in culture

05 October 2017

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The condition polycystic kidney disease, also known as PKD, has been recreated using stem cells in a culture dish by scientists in the US.

PKD is one of the most common causes of kidney disease among humans, affecting up to 1 in 600 people. It leads to the development during adulthood of numerous large cysts, which progressively replace the healthy kidney tissue and ultimately cause kidney failure requiring dialysis or transplantation. Cysts can also form in other organs too, including the brain and liver, and PKD patients are also at risk of brain aneurysms that can rupture and cause a haemorrhage.

The condition is transmitted genetically, and is a dominant trait, so a child with an affected parent has a 50%  chance of developing the disease. Two genes - PKD1 and PKD2 - have been linked to the condition, but scientists still do not understand how exactly they cause the condition, or whether it may be possible to halt the progression of PKD using drugs. 

Part of the reason for this is that there are very few "model systems", either in animals or in cell culture, that can accurately replicate the disease process itself, and the condition takes decades to develop in humans.

Recently, University of Washington scientist Benjamin Freedman and his colleagues have been exploring ways to better recreate PKD in the culture dish.

Starting with human stem cells, the team used gene editing techniques to deactivate the polycystin genes in their cells. Grown under the right conditions, these modified stem cells can be persuaded to turn into "mini kidneys", called renal organoids, in culture. These develop the same tiny tubes for filtering blood that are seen in an adult kidney. Critically, they can occasionally also produce cysts similar to those seen in some forms of PKD, although with a very low frequency (only about 7% of the time).

What surprised the Seattle-based scientists, though, was that if the developing mini-kidneys were lifted up from the plate surface and left bobbing about, unattached, in the culture medium they would begin to form massive, 1 centimetre in diameter cyst structures, 75% of the time (ten times more often).

This suggests that part of the disease mechanism that triggers the formation of cysts in PKD is the absence of some form of communication between the cell and its surroundings. "One of the genes linked to PKD codes for a receptor that 'reaches out' from the host cell and grabs onto other structures," says Freedman. "So maybe when that goes wrong it causes the cells to grow incorrectly." 

The great virtue of the Washington team's work, which was published this week in Nature Materials, is that it now offers a highly reproducible in-vitro model of PKD that can be used to investigate drugs and therapies which might be able to arrest the progression of the condition. "You can literally throw tens, hundreds or even thousands of drugs onto these mini-kidneys to see what happens," Freedman explains. "This is what we're doing now. In fact, we report in the paper on one chemical that dramatically accelerated the disease process."

Counter-intuitive as it sounds, that discovery is extremely powerful because, as Freedman points out, "if we know how to break things, we can work out how not to break things in future..."

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