In a study published in Science, USC researchers paired a biological discovery with an engineering feat to create more faithful, reproducible lab-grown kidney structures grown from stem cells, known as organoids. By mapping the developing human kidney, they identified a previously unrecognized developmental axis that helps organize the kidney's filtering units, or nephrons. They then engineered "synthetic organizer" cells to recreate aspects of this developmental environment in organoids.
This advance makes organoids more reliable models for studying disease and evaluating potential therapies, while supporting long-term efforts to generate transplantable kidney tissue.
"It is important that we're starting to get good reproducibility from organoid models that can lead to robust preclinical models of cell function and disease to benefit patients," said the paper's co-corresponding author Nils Lindström, PhD , assistant professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC.
Over the past decade, organoid work has relied on cells' ability to self-organize into tissue-like structures, often in response to adding chemicals and proteins that act broadly in the whole organoid. In contrast, the synthetic organizer serves as a localized and targeted source that secretes controllable amounts of specific Wnt proteins within the organoid itself. These are key signals that help shape the developing kidney. This creates a signaling environment much more similar to a naturally developing kidney and gives researchers a way to control where and how kidney structures form.
"With our approach, we are trying to control self-organization, and work with it as opposed to try to completely override it," said co-corresponding author Leonardo Morsut, PhD , associate professor of stem cell biology and regenerative medicine, and biomedical engineering at the Keck School of Medicine and USC Viterbi School of Engineering.
Following the signal
The project began by making tools to copy developmental signals. Postdoctoral researcher Fokion Glykofrydis from the Morsut Lab engineered a "synthetic organizer" cell that secreted a Wnt protein known to be present in the kidney, and graduate student Connor Fausto from the Lindström Lab proposed an experiment to test how this Wnt-secreting cell would affect organoid nephrons.
The experiments revealed that the synthetic organizer enabled two key processes essential for building organs: controlling the identity of cells and influencing the shape of developing structures.
Lindström expected Wnt to trigger nephrons to change their identity into cells capable of forming connections with the urine drainage system. What surprised him was that the nephrons also changed shape and elongated towards the source of the Wnt signal, which doesn't happen when signals are delivered uniformly to the whole organoid. Compared with the developmental process seen in traditional kidney organoids, this elongation towards the Wnt source is more similar to what happens in a naturally developing kidney.
"A single, localized signal did two things at once. It changed what the cells became and physically pulled the tubules toward the source," Lindström said. "You would not see that with a uniform chemical bath of signals."
Organizing an organoid
The team also identified a previously unrecognized axis, a direction along which the developing kidney organizes itself. Developmental biologists have long known about the nephron's classic "proximal-distal axis," which runs from its blood-filtering end to its urine-drainage end. The new axis is defined instead by how close each part of the nephron sits to the collecting duct, the tube system that drains urine and releases Wnt signals during development. Those signals tell the nephron what shape to take and which way to point.
"The study shows that there's an undiscovered axis that sets up how a nephron looks and forms," said Lindström. "It's not every day that you find something new in human development at that level."
Most kidney organoids contain only nephrons and lack the collecting duct that supplies this local Wnt signal, so they have no such axis and organize in a radially symmetrical pattern. By mapping how kidney cells respond to Wnt at specific locations in the developing kidney, the team recreated that environment in organoids with the synthetic organizer, producing structures that are both more developmentally faithful and more reproducible.
For Morsut, the synthetic organizer is one of several tools his lab is building to control how tissues form, and the one he is most excited about, because it steers development in a way that is powerful but not intrusive.
"The synthetic organizer is just a little cluster of cells that don't build anything themselves," said Morsut. "But they produce a powerful field that aligns the stem cells and gives them a direction."
Aligning cells is something embryos do repeatedly as they build themselves, he noted, and the study shows it can now be put to work in an engineering setting, steering the process toward a desired outcome.
The results, he said, have been nothing short of magical.
"At the beginning of my talks, I always show a video of embryonic development," said Morsut. "You start from a single cell, and you get to a complete organism, and that's as close to magic as it gets. Now, we open a possibility of controlling this magic technology for building organs. This study shows that we can do that, and I'm excited to see what others will do in other contexts."
About this research
All authors are from the Keck School of Medicine of USC. They include: Navneet Kumar, Jack Schnell, Reka L. Csipan, Faith De Kuyper, Minnal Kunnan, Manuel Pelayo, MaryAnne Achieng and Anoothi Seth from the Department of Stem Cell Biology and Regenerative Medicine; Brendan Grubbs and Matthew Thornton from the Department of Obstetrics and Gynecology; and Michael Thompson, Enmian Chang, Xuduo Wen and Kelly Street from the Department of Population and Public Health Sciences.
This work was supported by federal funding from the National Institutes of Health (grants NIDDK R01DK136802, NICHD T32HD060549, and NIGMS R35GM138256), the American Society of Nephrology/United States Department of Health and Human Services KidneyX, and the National Science Foundation (grant CBET-2145528 and CBET-2034495). Additional support came from the USC Department of Stem Cell Biology and Regenerative Medicine Startup Fund, renalART, the California Institute for Regenerative Medicine (grants INFR6.2-15400 and EDUC4-12756), the Wellcome Leap HOPE program, the USC Viterbi School of Engineering's Center for CIEBOrg, and the Chan Zuckerberg Initiative Donor Advised Fund of the Silicon Valley Community Foundation (grant 2023-332386). No federal funds were used for work related to human tissue.
Disclosures
Fausto, Glykofrydis, Lindström and Morsut are inventors on the declaration for U.S. nonprovisional patent application no. 19/396,812 (USPTO ref. no. 2025-028-02), submitted by the University of Southern California and covering "Compositions and methods for controlling patterning of human kidney organoid nephrons."
Certain research materials are available from USC under standard material transfer agreements.
