A USC Stem Cell-led research team have made a big breakthrough in their efforts to build mouse and human synthetic kidneys. In a new paper published in Cell Stem Cell, the scientists describe generating more mature and complex lab-grown organoids than ever before.
“This is a revolutionary tool for creating more accurate models for studying kidney disease, which affects one in seven adults,” said corresponding author Zhongwei Li, Associate Professor of Medicine and Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC. “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 U.S. awaiting transplant – the only cure for end-stage kidney disease.”
From organoids to ‘assembloids’
Scientists from the Li Lab had previously constructed organoids composed of nephrons, the kidney’s filtering units, as well as organoids resembling the kidney’s collecting ducts – which concentrate urine.
Now, led by first authors Biao Huang, Pedro Medina and Zipeng Zeng from the Li Lab and Jincan He from Tongji University in Shanghai, the team has successfully combined nephron and collecting duct components to produce what they have dubbed ‘assembloids.’
Growing kidneys in the lab and beyond
The researchers optimised conditions for growing mouse and human assembloids in the lab. They then transplanted the assembloids into living mice, where the structures matured further – growing larger and developing connective tissue and blood vessels.
By maturing the assembloids in the native environment of the body, we tapped into kidney progenitor cells’ natural ability to self-assemble
“By maturing the assembloids in the native environment of the body, we tapped into kidney progenitor cells’ natural ability to self-assemble,” said Li. “We believe this will be a key to succeeding in the complex endeavour of building functional synthetic kidneys.”
Both mouse and human assembloids demonstrated kidney-like functions, including blood filtration, uptake of proteins such as albumin, secretion of kidney hormones and early signs of urine production.
Beyond embryonic development
While previous kidney organoids only matured to an embryonic stage, the mouse assembloids achieved the same level of maturity as a new-born mouse kidney, based on gene activity and other benchmarks. Human assembloids also matured beyond the embryonic stage, though their precise level of maturity remains uncertain due to the lack of new-born human kidney samples for comparison.
Disease modelling potential
The study also shows that assembloids can serve as high-fidelity models for complex human kidney diseases. For example, the researchers grew human assembloids from cells with a single genetic change – the loss of a functional PKD2 gene – that causes autosomal dominant polycystic kidney disease (ADPKD).
These diseased assembloids developed large kidney cysts when grown in living mice and displayed advanced disease features such as inflammation and fibrosis – which had not previously been modelled in the lab.
“Our study provides a powerful new tool for studying a wide range of complex kidney diseases,” said Li, “as well as strong foundation for engineering functional synthetic kidneys as a lifesaving option for the patients who need them.”
