A research team supported by the National Institutes of Health has developed a new approach to better understand the biology of polycystic kidney disease (PKD), an often life-threatening genetic disorder that affects millions of people worldwide. The scientists combined two ways of modeling the disorder — organ-on-a-dish and organ-on-a-chip technologies — to show the role of glucose, a sugar commonly found in the blood, in cyst formation PKD. The results, published in Nature Communications, could lead to better ways to test and develop treatments for PKD and perhaps other diseases.
An organ in a dish, or organoid, is a miniature version of an organ grown in a laboratory dish. It can mimic key features of a human organ’s structure and function. Organs-on-a-chip, or tissue-chips, are more complex 3D models, containing live channels and cells, that aim to mimic the structure and environment of organs and tissues. NIH’s National Center for Advancing Translational Sciences (NCATS) research programs develop both technologies and approaches based on human cells to study disease and better predict whether drugs will be safe or toxic in humans.
In PKD, small tubes (tubules) in the kidneys expand like water balloons, forming sacs of fluid over decades. The sacs, or cysts, eventually expel healthy tissue, causing problems with kidney function and kidney failure. Scientists have identified many of the genes that cause PKD, but much is still unknown about the disease, including how the cysts form.
“We are able to summarize a complex process of tubule cyst formation in a process in a Petri dish that takes only a few weeks, but there has been a lack of technologies to study the disease further,” said the School of the University of Washington. Medical scientist Benjamin Freedman, Ph.D., who led the work. “Animal models are useful, but translating the results of these studies to people has been a challenge.”
Freedman, co-author Jonathan Himmelfarb, MD, and colleagues in Seattle decided to explore combining organoid technology with a tissue-on-a-chip platform. The scientists believe that fluid flow is important in the development of cysts, but they had no way to test the theory in organoids.
In the kidneys, fluid always passes through the tubules; at any given time the kidneys have about 25% of the body fluid flowing through them. We cannot reproduce this system in the plate because the fluid has to move through the kidney structures. Using microfluidic technology in tissue chips was the next natural step.”
Benjamin Freedman, Ph.D., scientist, Washington University School of Medicine
Freedman’s group showed that exposing the PKD-on-a-chip organoid model to a combination of water, sugar, amino acids and other nutrients caused the cysts to expand relatively quickly. They discovered that the cysts were absorbing glucose and pulling water from the fluid passing over them, causing the cysts to grow larger. Although glucose is generally absorbed by the kidneys, glucose absorption has not been linked to cyst formation in PKD.
“It wasn’t a big surprise that the cysts could take up glucose, but it was surprising that they depended on it. It’s a new way to think about how these cysts form,” Freedman said.
The scientists added fluorescent glucose to mice with PKD and found that the mouse cysts also took up the glucose. “We think the tubules are taking up fluid in mice, just like in organoids. The kidney gets bigger, and as the tubules expand to accommodate the expansion over time, cysts form,” he said. said Freedman.
Understanding the mechanisms of PKD may point to new ways to treat it. As part of the study, the research team showed that adding compounds that block glucose transport prevented cyst growth. Freedman noted that glucose inhibitors are being developed for other types of kidney disease.
“Researchers have shown that simulating fluid flow is essential to making this system more closely resemble the environment of the kidney with PKD,” said Danilo Tagle, Ph.D., director of the Office of Initiatives NCATS specials. “The combination of the two technologies makes tissue-chip technology more adaptable to drug discovery and drug development and allows researchers to take advantage of the strengths of both platforms. This holds great promise for studying other diseases in new ways in the future.”
Source:
National Institutes of Health
Journal reference:
Li, SR, et al. (2022) Glucose uptake drives cystogenesis in a human organoid-on-a-chip model of polycystic kidney disease. Communications of nature. doi.org/10.1038/s41467-022-35537-2.