Lab-grown ‘mini-kidneys’ unlock secrets of rare disease

Researchers have solved a medical mystery in a poorly understood disease by discovering which cells cause tumors in patients with tuberous sclerosis complex (TSC). As described in Cell Reports, they did this by creating genetically engineered kidney organoids, or “mini-kidneys” from human tissue.

“The cells that cause tumors in tuberous sclerosis have been a mystery for decades,” said lead author Dr. Bill Stanford, Principal Investigator at The Ottawa Hospital and Professor at the University of Ottawa. “Our results may help find possible treatment targets for this difficult disease.”

TSC is a rare genetic disease that causes benign tumors of the skin, brain, kidneys, heart or lungs. TSC tumors are very diverse, occurring in children or adults with a range of symptoms from mild to life-threatening and often include seizures and kidney problems. There is no cure and treatment options are limited.

“Kidney disease is the leading cause of death in patients with TSC. About 60-80% of patients develop tumors in their kidneys, often reducing kidney function and sometimes leading to catastrophic bleeding,” said Dr. Adam Pietrobon, MD-PhD student at The Ottawa Hospital and the University of Ottawa. “There were no adequate laboratory models to study how TSC affects the kidney, so we made one ourselves.”

TSC is caused by mutations in the TSC1 or TSC2 gene. For most patients, these mutations arise spontaneously during development or early life rather than being inherited from parents. This makes TSC a difficult disease to study. While lab researchers often use animals to study human disease, there was no animal model that fully captured the impact of TSC on the kidneys.

TSC tumors in the kidney have baffled experts because they are extraordinarily diverse in size, cell makeup and gene expression, even within the same patient. The causes of this diversity were unknown and this makes treatment difficult.

To better understand the impact of TSCs on the kidneys, the team cultured 3D kidney tissue in the lab from human stem cells genetically modified to have a TSC1 or TSC2 mutation. Known as organoids, these miniature, simplified versions of the kidneys had a similar genetic profile to the TSC tumors found in the patents. The researchers then took individual cells from these kidney organoids and injected them into the kidneys of mice, where they grew into human TSC tumors.

Using these organoids, the researchers revealed that cells called Schwann cell precursors are the starting point for TSC tumors in the kidney. They also discovered that this single mutation affects the development of many different cell types, which explains the variation in kidney tumors even within the same person.

“These ‘mini-kidneys’ can not only help us better understand this disease, but they can also be used to test new therapies,” said Dr Pietrobon.

Authors: Adam Pietrobon, Julien Yockell-Lelièvre, Trevor A. Flood, William L. Stanford

Basic resources: Human Pluripotent Stem Cell Laboratory, Stem Core, Bioinformatics Facility, High Content Imaging Core, Cell biology and image acquisition, Histology/pathology core

About The Ottawa Hospital

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About the University of Ottawa

The University of Ottawa has more than 54,000 students, professors and employees who live, work and study in French and English. Our campus is a crossroads of cultures and ideas, where bold minds come together to inspire breakthrough ideas. We are one of Canada’s top 10 research universities – our faculty and researchers explore new approaches to meet today’s challenges. As one of just a handful of Canadian universities ranked among the world’s top 200, we attract exceptional thinkers and welcome diverse perspectives from around the world. www.uottawa.ca

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