A research effort led by scientists from the Keck School of Medicine at the University of Southern California (USC) has led to the development of more mature and complex lab-grown kidney progenitor organoids. Building on previous work where they constructed organoids composed of nephrons as well as organoids resembling collecting ducts, the team now reports that they have combined both types of organoids to form new mouse and human structures dubbed “assembloids.”
Full details of the work are published in a new Cell Stem Cell paper titled “Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling.” The assembloids are “a revolutionary tool for creating more accurate models for studying kidney disease,” said Zhongwei Li, PhD, corresponding author on the study and associate professor of medicine, and stem cell biology and regenerative medicine at the Keck School of Medicine of USC. These developments are a critical part of the group’s “long-term goal of building a functional synthetic kidney for more than 100,000 patients in the U.S. awaiting transplant,” he added.
A key step in the scientists’ work was optimizing the conditions needed to grow the assembloids. They then transplanted the mouse and human assembloids into live mice, and observed how the assembloids grew and matured, including the development of connective tissue and blood vessels. According to the paper, both transplanted mouse and human assembloids exhibited kidney-like functions such as blood filtration, protein uptake, hormone secretion, and early signs of urine production.
“By maturing the assembloids in the native environment of the body, we tapped into kidney progenitor cells’ natural ability to self-assemble,” Li said, adding that “we believe this will be a key to succeeding in the complex endeavor of building functional synthetic kidneys.”
Furthermore, gene expression data and other forms of evidence show that while previous kidney organoids only matured to an embryonic state, the mouse assembloids reached the same level of maturity as a newborn mouse kidney. Human assembloids also matured beyond the embryonic stage, although their precise maturity level could not be determined due to the lack of available newborn human kidney samples.
The scientists also reported results from experiments that demonstrate that assembloids can work as high-fidelity models for studying complex human kidney diseases. Specifically, they report growing human assembloids from cells that were edited to remove a functional PKD2 gene. The loss of this gene causes autosomal dominant polycystic kidney disease, a genetic condition where the kidneys develop multiple large cysts that impair their function.
According to the team, the transplanted diseased assembloids grew into large human kidney cysts in the mice and exhibited complex disease features such as inflammation and fibrosis. This is particularly noteworthy since these features could not be modeled before.
“Our study provides a powerful new tool for studying a wide range of complex kidney diseases,” said Li, “as well as [a] strong foundation for engineering functional synthetic kidneys as a lifesaving option for the patients who need them.”
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