NKF-Supported Research: Mini-Kidney Organoids from Stem Cells Recreate Human Disease in a Dish
Using kidney organoids grown from stem cells and gene editing, scientists have for the first time re-created human kidney disease in a petri dish.
The findings pave the way for personalized kidney regeneration and drug discovery.
Boston, MA and Seattle, WA (October 23, 2015) – For the first time, investigators at the Brigham and Women’s Hospital, Harvard Medical School, and the University of Washington have successfully grown mini-kidney ‘organoids’ that re-create human kidney disease in a petri dish. The findings, which combine stem cell biology with cutting-edge gene-editing techniques, are reported in the journal Nature Communications.
The mini-kidney organoids were grown from pluripotent stem cells, personalized cells that have ‘turned back the clock’ to a time when they could become any type of organ in the body. When treated with a chemical cocktail, these stem cells matured into structures that resembled miniature kidneys. These mini-kidney organoids contained tubules, filtering cells, and blood vessel cells, and could transport chemicals and respond to toxic injury similar to kidney tubules in patients.
“A major unanswered question was whether we could re-create human kidney disease in a petri dish using this technology,” says Dr. Benjamin Freedman, PhD, lead author on the study, now an Assistant Professor in the Division of Nephrology, Department of Medicine at the University of Washington. “Answering this question was important for understanding the potential of mini-kidneys for clinical kidney regeneration and drug discovery.”
To re-create human disease, Freedman and colleagues used a new gene-editing technique called CRISPR to engineer mini-kidneys with genetic changes linked to two common kidney diseases, polycystic kidney disease and glomerulonephritis. Organoids with mutations in polycystic kidney disease genes formed cysts (balloon-like sacs of fluid) from kidney tubules. Organoids with mutations in podocalyxin, a gene linked to glomerulonephritis, lost connections between filtering cells. The genetically engineered mini-kidneys thus re-created specific characteristics of each human disease in a petri dish.
“Mutation of a single gene results in changes in kidney structures associated with human disease, allowing better understanding of the disease and serving as models to develop therapeutic agents to treat these diseases,” explains Dr. Joseph Bonventre, MD, PhD, senior author on the study and Chief of the Renal Division at Brigham and Women’s Hospital at Harvard.
"These genetically engineered mini-kidneys have taught us that human disease boils down to simple components that can be re-created in a petri dish,” adds Freedman. “This provides us with faster, better ways of testing out drugs and therapies that might work in humans.”
Importantly, genetically-matched kidney organoids that did not possess disease-linked mutations showed no signs of either disease. “CRISPR can be used to correct genetic mutations,” explains Freedman. “Our findings suggest that gene correction using CRISPR may be a promising new therapeutic strategy.”
Kidney disease costs the United States 40 billion dollars per year and affects 700 million people worldwide. Twelve million patients have polycystic kidney disease and two million people have complete kidney failure. Dialysis and kidney transplantation, the only options for kidney failure patients, can cause harmful side effects and poor quality-of-life.
“As a result of this new technology, we can now grow new kidney tissue on-demand, which is 100 % immunocompatible with our own bodies,” says Freedman. “We have shown that these tissues can mimic both healthy and diseased kidneys, and the organoids can survive in the mouse after being transplanted. The next question is whether they can perform the functions of the kidney after transplantation.”
Study co-authors include Drs. Paul Lerou, Jing Zhou, Theodore Steinman, Kelly McNagny, Kiran Musunuru, Craig Brooks, Albert Lam, Hongxia Fu, and Ryuji Morizane.
Disclosures: Joseph Bonventre hold patents on kidney injury molecule-1 which have been assigned to Partners Healthcare. The remaining authors declare no competing interests. The work was supported by the National Institutes of Health, the National Kidney Foundation, the Harvard Stem Cell Institute, the Institute for Stem Cell and Regenerative Medicine (University of Washington), the Kidney Research Institute (University of Washington), and The Biomedical Research Centre (University of British Columbia).