OTTAWA, Ontario — Tiny, lab-grown kidneys have helped scientists discover the cause of a mysterious genetic disease.
Researchers in Canada say they used these genetically engineered kidney organoids (or “mini kidneys”) to figure out what causes patients with tuberous sclerosis complex (TSC) to develop tumors throughout their bodies. TSC is a rare condition which causes benign tumors to grow in the skin, brain, kidneys, heart, and lungs.
TSC tumors are also very diverse, developing in either children or adults. These patients have a range of symptoms, from mild to life-threatening, including seizures and kidney failure. Currently, there is no cure for TSC.
“The cells at the origin of tuberous sclerosis tumors have been a mystery for decades,” says senior author Dr. Bill Stanford, senior scientist at The Ottawa Hospital and professor at the University of Ottawa, in a media release. “Our results can help find possible treatment targets for this challenging disease.”
“Kidney disease is the leading cause of death in patients with TSC. Around 60 to 80 percent of patients develop tumors in their kidneys, often reducing kidney function and sometimes leading to catastrophic bleeding,” adds lead Dr. Adam Pietrobon, MD-PhD student at The Ottawa Hospital and the University of Ottawa. “There were no adequate lab models to study how TSC affects the kidney, so we made one ourselves.”
A single genetic mutation is to blame
Researchers say TSC is the result of a mutation in the TSC1 or TSC2 gene. Most patients see this mutation develop on its own during childhood instead of inheriting it from a parent. This actually makes it harder for scientists to study. Moreover, there aren’t any animal models which fully capture TSC’s impact on human kidneys.
The tumors in the kidneys have been a mystery to researchers because of their diversity in size, cellular makeup, and gene expression. Doctors even spot differences between multiple tumors in a single patient.
To figure out what causes the tumors to be so diverse, the researchers grew their own 3D kidney tissues in a lab from human stem cells. The mini kidneys were also genetically engineered to have a TSC1 or TSC2 mutation. Simply put, organoids are miniature versions of organs scientists grow artificially. In this case, the lab-grown kidneys had the same genetic profile as someone with TSC tumors.
Study authors took single cells from the kidney organoids and injected them into the kidneys of mice. The cells grew into human TSC tumors.
Through this process, the team discovered that special cells called Schwann Cell Precursors are where TSC tumors develop in the kidney. Moreover, this single mutation affects the development of several different kinds of cells in the body. Researchers say this finally explains why the disease causes so many different types of tumors to grow within a single patient.
“Not only can these ‘mini-kidneys’ help us to better understand this disease, they can also be used to test new therapies,” Dr. Pietrobon concludes.
The study is published in the journal Cell Reports.