Scientists develop advanced lab-grown kidney organoids for disease research

A team led by USC Stem Cell scientist Zhongwei Li, PhD, has produced some of the most complex and mature lab-grown kidney models to date. Supported by a three-year grant from the California Institute for Regenerative Medicine (CIRM), Li and his colleagues are now mapping the characteristics, structure and function of these mini-kidney structures, known as human synthetic kidney organoids (hSKOs), to show how they can advance research on disease.

The hSKOs, tiny organ-like structures grown from human stem cells, could eventually contribute to efforts to build replacement organs for transplant patients, while more immediately providing a powerful way to study kidney disease. This includes chronic kidney disease (CKD), which affects 1 in 7 U.S. adults and disproportionately impacts minority populations, as well as autosomal-dominant polycystic kidney disease (ADPKD), an inherited condition where large cysts interfere with kidney function.

This new model has features not seen in other kidney organoids, because structures are arranged in the right pattern and connected to one another. That organization is essential for replicating the organ's function."

Zhongwei Li, PhD, associate professor of medicine and stem cell biology and regenerative medicine at the Keck School of Medicine of USC and the project's principal investigator

Growing synthetic kidney organoids

Reproducing the structure and function of the kidney, one of the body's most complex organs, has proved a challenge. The kidney filters waste from the blood and produces urine using multiple cell types that must be organized and connected in the right way. Earlier organoids could recreate some parts of the system, but could not link them together.

This changed last year, when Li and his collaborators reported the creation of hSKOs (also known as human kidney progenitor assembloids, or hKPAs) combining kidney filtering and urine collecting structures in the journal Cell Stem Cell. They mimicked some of the kidney's intricate structure and filtered blood when transplanted into mice. The findings were praised by other researchers, who suggested that these organoids may be the most authentic kidney models created so far.

Li's approach to developing hSKOs was inspired by the way kidneys form in the developing embryo. Because embryonic kidney cells are highly self-organizing and naturally arrange themselves into the right pattern, he reasoned that he simply needed to bring the right cells together under the right growth conditions.

Li and his colleagues worked meticulously over the past decade to refine two types of kidney progenitor cells, or early-stage cells that can develop into specific kinds of kidney tissue. They created organoids from , which develop into the kidney's filtering units, and separate organoids from , which form the structures that carry urine. The researchers also tested many chemical formulas to create a nutrient-rich "bath" that supported complex and organized networks of cells.

Bringing these two types of organoids together under the right lab conditions produced a kidney-like system, which they then transplanted into living mice to further mature. The hSKOs displayed patterns of gene activity, hormone production and other biological functions with some similarity to those seen in mouse and human kidneys.

Advancing research on kidney disease

Over the next three years, the team will study how hSKOs mature over time and test how well they carry out key kidney functions.

They will also use hSKOs to model PKD, which is difficult to study because researchers can typically only access tissue samples from the disease's latest stages.

"It's important to intervene at the early stages of a disease, but we haven't had tools that allow us to study this period of PKD. Our organoids may change that," Li said.

Using advanced genetic and molecular analysis tools, the team will observe how the first cysts form and explore potential treatment strategies for PKD.

In addition, the team will generate hSKOs from eight stem cell lines representing male and female Caucasian, African American, Hispanic and Asian populations. This will provide opportunities to study kidney disease across different populations.

Beyond research on kidney disease, working kidney organoids can offer a powerful way to streamline clinical trials across the pharmaceutical industry by predicting which drugs will be toxic in humans. Currently, around 1 in 10 investigational drugs fails in clinical trials because of kidney toxicity, leading to lost time, money and effort.

"If these models can accurately predict kidney toxicity before a drug enters clinical trials, they could make a major contribution to drug development," Li said.

In the long term, organoids may someday form the basis for a transplantable lab-grown kidney replacement.