Using bioprinted organoids to learn about the body's regenerative potential

Why do some patients with acute kidney failure recover while others develop chronic kidney disease? As animal models are unable to answer this important question, researchers at the BIH Center for Regenerative Therapies (BCRT) are now developing a ‘human’ alternative: miniature kidneys, manufactured using pluripotent stem cells and a 3D bioprinter. The first experiments using the new 3D model are likely to be conducted in approximately 12 months’ time.

The regenerative capacity of the human body is remarkable. Even after acute kidney failure (also known as acute kidney injury, or AKI), many people will see their kidneys make a full recovery. Acute kidney failure can develop after surgery and is also a common complication of severe COVID-19.

However, there is only a 50 percent chance that the kidneys will regenerate fully after this type of injury. This means that one in two patients will develop chronic kidney disease. In some cases, this will lead to the complete loss of kidney function and the need for dialysis. Researchers have so far been unable to determine why some kidneys will regenerate while others will not. Knowledge of the underlying secrets might enable researchers to develop new treatments.

The only problem is that, until now, the study of acute and chronic kidney disease has relied on animal models. These, however, fail to accurately reflect what happens in the human body, meaning that results are not transferable to humans.

It’s all about regenerative therapies
A case for Dr. Andreas Kurtz and his team from the stem cell research laboratory at Charité’s BIH Center for Regenerative Therapies (BCRT). Working alongside his colleagues, Dr. Bella Roßbach and Dr. Krithika Hariharan, the biologist is using stem cell technology to develop small kidneys of human tissue origin. The aim is to enable large-scale research into kidney disease.

Explaining the aim of their endeavors, Dr. Kurtz says: “We want to develop regenerative medicine treatments. For this, we need a human model which recreates, in as life-like a manner as possible, the kidney’s natural regenerative capacity and the disease processes involved.” He adds: “We are currently in the process of developing and testing a 3D model of this kind.”

Remarkable similarities with human kidneys
The building blocks of these innovative models are ‘pluripotent stem cells’. These can be produced in the laboratory by reprogramming cells which have been isolated from donor tissues such as skin, blood or hair follicles. As true ‘all-rounders’, these pluripotent stem cells can be differentiated into kidney cells. This process takes place on small trays and produces tiny organoids. The results are astonishing - even to the researchers themselves. “Kidneys grown from stem cells do look exactly like human kidneys, just much, much smaller,” emphasizes Dr. Kurtz.

However, there is one other way in which these organoids differ from an adult kidney. The organoids are at the fetal stage of development, i.e. they are immature and ought to be allowed to grow and mature. This, however, remains impossible, for practical reasons. The organoids also lack a functioning circulatory system, which is important for the formation of the kidney’s filtration system. This problem of lack of perfusion in organoids remains unresolved but is the focus of many research groups across the globe, including those at the BCRT.

New technologies simulate kidney function
In the absence of such models, Berlin-based researchers are making do with 3D bioprinted kidneys. To make these, the researchers must first isolate certain cells from the organoids. These are then used to bioprint individual kidney components. In this case, the kidney’s filtration units. These partial organoids are then combined with a ‘HAKI chip’, which simulates normal kidney perfusion, i.e. the system which supplies the kidney with blood and other fluids. “Using the 3D printed kidney compartments with the perfusion unit enables us to produce a decent model of the kidney’s blood-filtering function,” says Dr. Kurtz.

Some fine-tuning will be required before the researchers can start to perform experiments using their organoids. Dr. Kurtz estimates this process will take approximately one year, adding that: “By then, we will hopefully be able to use our model to learn how kidney regeneration works, which factors play a role in it, and how we may be able to help patients in whom these processes do not work properly.”

Research without a single animal-based experiment.
Help for patients might come from new drugs which stimulate regenerative processes, or from cell-based treatments. Dr Kurtz observes: “The good thing is that, in addition to being able to study underlying mechanisms, we can also use our human model to test new treatments. And all of this is possible without a single animal-based experiment.”

(Text: Beatrice Hamberger)
 

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