A University of Southern California (USC) team led by Zhongwei Li has taken a major step toward building functional synthetic kidneys.
In a new Cell Stem Cell paper, researchers described generating the most mature and complex lab-grown kidney structures to date — so-called “assembloids” that combine the kidney’s filtering and urine-concentrating components.
Li, who studies stem cell biology and regenerative medicine at the Keck School of Medicine of USC, told DDN the breakthrough offers both immediate and long-term value.
“This is a revolutionary tool for creating more accurate models for studying kidney disease, which affects one in seven adults,” Li said. “It’s also a milestone towards our long-term goal of building a functional synthetic kidney for the more than 100,000 patients in the US awaiting transplant — the only cure for end-stage kidney disease.”
From organoids to assembloids
The team, led by first authors Biao Huang, Pedro Medina, and Zipeng Zeng from the Li lab, and Jincan He from Tongji University, previously produced individual organoids resembling nephrons, which function as collecting ducts. The new work combines both components to form assembloids that more closely mimic a functioning kidney.
In culture and following transplantation into mice, the assembloids grew larger and developed blood vessels and connective tissue. Both mouse and human assembloids demonstrated kidney-like activity, including blood filtration, protein uptake, hormone secretion, and early urine production.
Li said the leap in maturity sets this model apart. “Existing organoids are equivalent to an early embryonic kidney in gene expression, but the transcriptome of the mouse kidney progenitor assembloid (mKPA) is similar to that of a newborn mouse,” he said. “Because of the improved maturity, we noticed the expression of many transporters that play critical roles in kidney functions, such as organic anion transporters, organic cation transporters, SGLT2 (sodium-glucose cotransporter-2), are now expressed in mKPAs in vitro and in vivo.”
He added that this level of maturity enables validation of a “near complete set of kidney functions including glomerular filtration, tubular reabsorption and excretion, and endocrine functions, that were not observed in existing mouse kidney organoids.”
Applications in disease and drug discovery
The study provided proof of concept for modeling polycystic kidney disease (PKD). Human assembloids grown from PKD2-mutant cells recapitulated cyst growth, inflammation, and fibrosis — disease features that earlier models could not reproduce.
“This is the first model to be able to capture kidney fibrosis, which is a key feature of the pathogenic progression of chronic kidney disease (CKD),” Li said. “This is also the first time that interactions between [mouse] immune cells and human kidney disease is recapitulated. This model opens new doors to study these disease aspects.”
Beyond PKD, Li noted that the platform can be adapted to other genetic kidney disorders and could prove valuable for drug discovery. “Based on this advanced model, we are now working with partners from academia and industry to study PKD pathogenesis, screen, and validate drug candidates,” he said. “This model will also be valuable for accurate prediction of drug toxicity on the kidney, which is a major concern in drug discovery.”
Toward synthetic kidneys
Looking ahead, scaling remains the biggest barrier. “We are now trying to solve two critical challenges — how to scale the production of hundreds of thousands of nephrons from the hundreds that we can produce in each organoid; and how to drain the urine produced outside of the body in a directional way,” Li said.
Ultimately, Li’s lab has positioned assembloids not only as a powerful tool for disease modeling and drug testing, but also as a crucial stepping stone toward the long-term goal of engineering synthetic kidneys — and perhaps other organs — for patients who need them most.
