A team led by USC stem cell scientist Dr. Zhongwei Li has created some of the most complex and mature laboratory-cultured kidney models to date. With the support of a three-year grant from the California Institute for Regenerative Medicine (CIRM), Lee and colleagues are now mapping the properties, structure, and function of these mini-kidney structures, known as human synthetic kidney organoids (hSKOs), to show how they can advance disease research.
hSKO, small organ-like structures grown from human stem cells, could ultimately contribute to efforts to build replacement organs for transplant patients, while also providing a more immediate and powerful way to study kidney disease. These include chronic kidney disease (CKD), which affects one in seven adults in the United States and disproportionately affects a minority, and autosomal dominant polycystic kidney disease (ADPKD), a genetic disorder in which large cysts interfere with kidney function.
This new model has features not seen in other kidney organoids, as the structures are arranged in the correct pattern and interconnected. That tissue is essential for reproducing organ function. ”
Dr. Zhongwei Li, Associate Professor of Medicine, Stem Cell Biology, and Regenerative Medicine, Keck School of Medicine, University of Southern California, Project Principal Investigator
Growth of synthetic kidney organoids
Replicating the structure and function of one of the body’s most complex organs, the kidney, has proven difficult. The kidneys filter waste products from the blood and produce urine using multiple types of cells that are organized and connected in the right way. Previous organoids could reproduce parts of the system, but they could not be linked together.
That changed last year when Lee and his collaborators reported in the journal Cell Stem Cell the creation of hSKOs (also known as human kidney progenitor cell aggregates, or hKPAs), which combine the kidney’s filtration and urine collection structures. They mimicked some of the kidney’s complex structures and filtered blood when transplanted into mice. This discovery was praised by other researchers, who suggested that these organoids may be the most authentic kidney model ever created.
Li’s approach to hSKO development was inspired by the way the kidney forms in the developing embryo. He reasoned that fetal kidney cells are highly self-organized and naturally arrange themselves into appropriate patterns, so all you need to do is collect the right cells under the right growth conditions.
Over the past decade, Lee and his colleagues worked meticulously to purify two types of kidney progenitor cells, or early-stage cells, that can develop into specific types of kidney tissue. They created organoids from the kidney that develop into the filtration unit of the kidney, and isolated organoids from the kidney that form the urine-carrying structures. The researchers also tested a number of chemical formulas to create nutrient-rich “baths” that support complex, organized cell networks.
Combining these two types of organoids under appropriate laboratory conditions produced a kidney-like system, which was then transplanted into live mice for further maturation. hSKO showed patterns of gene activity, hormone production, and other biological functions that were somewhat similar to those seen in mouse and human kidneys.
Research on kidney disease progresses
Over the next three years, the research team will study how hSKO matures over time and test how well it performs important kidney functions.
They also plan to use hSKO to model PKD, which is difficult to study because researchers typically only have access to tissue samples from the latest stages of the disease.
“It is important to intervene early in the disease, but we don’t yet have tools that allow us to study this phase of PKD. Our organoids may change that,” Lee said.
The research team will use advanced genetic and molecular analysis tools to observe how the first cyst forms and explore potential treatment strategies for PKD.
In addition, the team generates hSKO from eight stem cell lines representing Caucasian, African American, Hispanic, and Asian male and female populations. This provides an opportunity to study kidney disease across different populations.
Beyond kidney disease research, functioning kidney organoids could provide a powerful way to streamline clinical trials across the pharmaceutical industry by predicting which drugs are toxic to humans. Currently, approximately 1 in 10 investigational drugs fail in clinical trials due to nephrotoxicity, resulting in loss of time, money, and effort.
“If these models can accurately predict kidney toxicity before a drug enters clinical trials, it could make a significant contribution to drug development,” Lee said.
In the long term, organoids may one day form the basis of transplantable, laboratory-cultured kidney replacements.
sauce:
Keck School of Medicine, University of Southern California
Reference magazines:
Fan, B. Others. (2025). Spatially patterned kidney aggregates recapitulate progenitor cell self-assembly and enable high-fidelity in vivo disease modeling. cell stem cells. DOI: 10.1016/j.stem.2025.08.013. https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(25)00328-5
