USC Scientists Create Most Advanced Lab-Grown Kidney Structures with Real Function for Disease Modeling
核心洞察
USC (搜索) researchers have developed the most mature and complex lab-grown kidney structures to date, called "assembloids," which combine filtering and urine-concentrating components to more closely mimic functioning kidneys.
The assembloids demonstrated kidney-like functions including blood filtration, protein uptake, hormone secretion, and early urine production when grown in culture and transplanted into mice.
These structures successfully modeled polycystic kidney disease (搜索) features like cyst growth, inflammation, and fibrosis that previous organoid models could not reproduce.
University of Southern California researchers have achieved a major breakthrough in kidney regenerative medicine by creating the most advanced lab-grown kidney structures to date. The team, led by Zhongwei Li from the Keck School of Medicine (搜索), developed sophisticated "assembloids" that combine multiple kidney components and demonstrate real kidney function both in laboratory culture and when transplanted into living mice.
Revolutionary Assembloid Technology
The research team, including first authors Biao Huang, Pedro Medina, and Zipeng Zeng from the Li lab, along with Jincan He from Tongji University (搜索), successfully combined nephron organoids with collecting duct components to create these advanced structures. Previous work by the Li lab had produced individual organoids resembling either nephrons (the kidney's filtering units) or collecting ducts (which concentrate urine), but the new assembloids represent the first successful integration of both components.
"This is a revolutionary tool for creating more accurate models for studying kidney disease (搜索), which affects one in seven adults," Li explained. "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 (搜索)."
Enhanced Maturity and Function
The assembloids demonstrated unprecedented maturity compared to existing kidney organoids. While previous models only achieved gene expression equivalent to an early embryonic kidney, the mouse kidney progenitor assembloids (mKPAs) showed transcriptome similarity to newborn mouse kidneys.
This enhanced maturity enabled expression of critical kidney transporters including organic anion transporters, organic cation transporters, and SGLT2 (搜索) (sodium-glucose cotransporter-2 (搜索)) both in laboratory culture and after transplantation. The assembloids validated "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," according to Li.
When transplanted into mice, both mouse and human assembloids grew larger and developed blood vessels and connective tissue. They demonstrated multiple kidney-like functions including blood filtration, uptake of proteins such as albumin, secretion of kidney hormones, and early signs of urine production.
Disease Modeling Breakthrough
The study provided compelling proof of concept for modeling complex kidney diseases. Human assembloids grown from PKD2 (搜索)-mutant cells successfully recapitulated the progression of autosomal dominant polycystic kidney disease (搜索) (ADPKD), developing large kidney cysts and displaying advanced disease features including inflammation and fibrosis when grown in living mice.
"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 (搜索) (CKD)," Li noted. "This is also the first time that interactions between [mouse] immune cells and human kidney disease (搜索) is recapitulated. This model opens new doors to study these disease aspects."
The ability to model these complex disease features represents a significant advancement over previous organoid systems, which could not reproduce the full spectrum of kidney disease (搜索) pathology.
Drug Discovery Applications
Beyond disease modeling, the assembloid platform offers significant potential for pharmaceutical research and development. Li indicated that his team is already collaborating with academic and industry partners to study PKD pathogenesis and screen drug candidates using this advanced model system.
"This model will also be valuable for accurate prediction of drug toxicity on the kidney, which is a major concern in drug discovery," Li explained. The enhanced maturity and functional complexity of the assembloids could provide more reliable preclinical testing platforms for evaluating both therapeutic efficacy and potential nephrotoxicity.
Future Challenges and Synthetic Kidney Development
While the assembloid technology represents a major advancement, significant challenges remain for scaling toward therapeutic applications. Li identified two critical hurdles: scaling production from hundreds of nephrons per organoid to the hundreds of thousands needed for a functional synthetic kidney, and developing methods to drain urine produced outside the body in a directional manner.
"By maturing the assembloids in the native environment of the body, we tapped into kidney progenitor cells' natural ability to self-assemble," Li said. "We believe this will be a key to succeeding in the complex endeavour of building functional synthetic kidneys."
The research positions assembloids not only as powerful tools for disease modeling and drug testing but also as crucial stepping stones toward engineering synthetic kidneys for patients with end-stage kidney disease (搜索). The work was published in Cell Stem Cell and represents a collaborative effort between USC (搜索) and Tongji University (搜索) researchers.