Organoid research to combat kidney disease
Can organoids help us better understand and treat kidney disease? This is the question Fjodor Yousef Yengej addressed during his PhD research in the , supervised by Hans Clevers (Hubrecht Institute), (UMC Utrecht), and (UMC Utrecht). On October 14th, he was awarded the cum laude distinction after successfully defending his thesis 鈥極rganoids: Translation to clinical nephrology鈥.
Kidney disease is common: in the Western world, it affects approximately one in six people. When a person鈥檚 kidney function deteriorates significantly, this is called kidney failure, requiring a kidney transplant or dialysis. These are intensive treatments with significant drawbacks. Research into better treatments for kidney disease is therefore urgently needed. To achieve this effectively, scientists must be able to mimic the human kidney as closely as possible in the laboratory, which is challenging for this particularly complex organ.
Tiny kidneys in the lab
During his PhD, Yousef Yengej investigated whether he could achieve this with organoids: miniature organs grown in the lab that closely resemble the real organ. To grow kidney organoids, Yousef Yengej used the cells responsible for kidney renewal and repair: adult stem cells. 鈥淭hese are present in everyone鈥檚 body and can be obtained from a small kidney biopsy or even from urine,鈥 he explains. 鈥淭he kidney organoids we grow from them are called tubuloids, because they consist of cells from the renal tubule. This is an important part of the kidney, where all the delicate transport of salts, buffers, fluids, and waste products takes place.鈥
Yousef Yengej鈥檚 research builds on the work of his predecessor, who was the first to successfully grow tubuloids. To make them resemble human kidney tubules even more closely, Yousef Yengej improved the culture conditions. He did this, for example, by adding hormones that also control the kidney in our bodies. Using these renal tubules, he was then able to study key kidney functions in the lab, such as salt transport, urine concentration, and waste excretion. By simulating salt transport, it also became possible to investigate the effects of diuretics, drugs for high blood pressure and heart failure.
Renal tubules on a chip
To further enhance the resemblance to real kidney tubules, Yousef Yengej also grew the tubuloids on an organ chip. 鈥淭ubuloids are small spheres in a lab dish, but a kidney tubule is 鈥 as the name suggests 鈥 tubular,鈥 he explains. 鈥淎n organ chip is a synthetic plate with small channels in it, where the cells grow. This gives them the shape of microscopic kidney tubules.鈥 Another advantage of the chips is that researchers can simulate the flow of blood and urine, making it even more similar to the real situation in the human kidney.
Diseased tubuloids
The next step was to mimic kidney disease in the tubuloids. Yousef Yengej and his colleagues demonstrated, for example, that they could grow tubuloids from patients with the kidney disease cystinosis, a hereditary metabolic disorder. These organoids proved suitable for mimicking the disease and for testing the effectiveness and safety of a new combination treatment. Yousef Yengej also investigated the drug lithium, which is used for mental disorders but can cause kidney damage as a side effect. 鈥淲e observed the known effects of lithium in the tubuloids and also discovered new mechanisms that contribute to the side effects,鈥 says the researcher.
What鈥檚 next?
Yousef Yengej predicts that scientists will be able to better investigate human kidney function and disease using renal tubuloids. 鈥淭he goal, of course, is to improve treatments for kidney disease,鈥 he says. 鈥淚t might even be possible to build pieces of kidney or an entire kidney to replace damaged tissue, but that is still in the distant future.鈥 Organoids from other organs, such as the intestine, could also play a role, as kidney damage isn鈥檛 always caused by diseases of the kidney itself. 鈥淭o treat or prevent kidney damage, it鈥檚 also important to look at the interaction between organs. This is something we鈥檙e also working on. For example, we鈥檙e looking at fat absorption in the intestine with the aim of finding new treatments for metabolic syndrome and diabetes, two major causes of kidney damage,鈥 he says.
Inspiration inside and outside the lab
Yousef Yengej says he experienced his PhD as a special, inspiring time. 鈥淚 have been given every opportunity to do very interesting research,鈥 he says. 鈥淎 highlight was the culmination of years of work in this dissertation.鈥 He also greatly enjoyed collaborating with colleagues. 鈥淚 was surrounded by driven, passionate people. Such an environment is very contagious for becoming enthusiastic about science.鈥 Outside the lab, Yousef Yengej also drew energy from collaboration. For example, he contributed to a podcast (Dutch) for the 木瓜福利影视 of the Netherlands and a for the Dutch Kidney Association, sharing his work with the general public and kidney patients. 鈥淚 really enjoyed doing that. It鈥檚 very motivating to see that people are interested in your research and to see what you鈥檙e doing it for,鈥 he concludes.
Yousef Yengej is celebrating obtaining his PhD with his family and friends. He is currently specializing in internal medicine, with the aim of further developing his knowledge of kidney diseases as a nephrologist. He would love to combine organoid research with his work as a doctor in the future.