Organoids to understand kidney diseases!

Polycystic kidney disease affects 12 million people. Until recently, scientists have been unable to recreate the progression of this human disease in a laboratory setting.

That scientific obstacle is being overcome. A report in Nature Materials shows that creating and manipulating mini-kidney organoids that contain a realistic micro-anatomy, researchers can now track the early stages of polycystic kidney disease. The organoids are grown from human stem cells..

"Beforehand, we had shown that these organoids could form PKD-like cysts, but what's new here is that we've used the model to understand something fundamental about that disease," said the senior author.

As one example, the team found that PKD mini-kidneys grown in free-floating conditions formed hollow cysts that were very large. These cysts could easily be seen. In contrast, PKD mini-kidneys attached to plastic dishes stayed small.

According to the lead author of the paper, other manipulations to the organoid also affect the progression of polycystic kidney disease.

Authors show that systematic substitution of physical components can dramatically increase or decrease cyst formation, unveiling a critical role for microenvironment in PKD. Removal of adherent cues increases cystogenesis 10-fold, producing cysts phenotypically resembling PKD that expand massively to 1-centimetre diameters. Removal of stroma enables outgrowth of PKD cell lines, which exhibit defects in PC1 expression and collagen compaction. Cyclic adenosine monophosphate (cAMP), when added, induces cysts in both PKD organoids and controls.

"We've discovered that polycystin proteins, which are causing the disease, are sensitive to their micro-environment," the lead explained. "Therefore, if we can change the way they interact or what they are experiencing on the outside of the cell, we might actually be able to change the course of the disease."

In another paper to be published in Stem Cells, the team discuss how podocytes, which are specialized cells in the body that filter blood plasma to form urine, can be generated and tracked in a lab environment. Study of gene-edited human kidney organoids showed how podocytes form certain filtration barriers, called slit diaphragms, just as they do in the womb. This might give the team insight into how to counter the effects of congenital gene mutations that can cause glomerulosclerosis, another common cause of kidney failure.

Taken together, these papers are examples of how medical scientists are making progress toward developing effective, personalized therapies for polycystic kidney disease and other kidney disorders.

"We need to understand how PKD works," senior author said. "Otherwise, we have no hope of curing the disease."

"And our research," he added, "is telling us that looking at the outside environment of the kidney may be the key to curing the disease. This gives us a whole new interventional window.

https://www.nature.com/nmat/journal/vaop/ncurrent/full/nmat4994.html