First-ever grafting of human ‘organoid’ tissue to a mouse model produces healthy, fully functional intestine
Researchers at Cincinnati Children’s have achieved an important milestone in the quest to develop replacement organs grown from a person’s own cells.
A team of scientists led by Michael Helmrath, MD, has successfully engrafted “organoids” of human intestinal tissue grown from pluripotent stem cells cultured in a lab dish to the kidney of a mouse. The mouse provided the blood supply to allow the organoid cells to grow into otherwise fully mature human intestinal tissue. This step represents a major advancement towards the development of a line of regenerative medicine that researchers in Cincinnati and around the world have been working for several years to develop.
Detailed findings were published online today, Oct. 19, 2014, in the journal Nature Medicine.
“These studies support the concept that patient-specific cells can be used to grow intestine,” Helmrath says. “This provides a new way to study the many diseases and conditions that can cause intestinal failure, from genetic disorders appearing at birth to conditions that strike later in life, such as cancer and Crohn’s disease. These studies also advance the longer-term goal of growing tissues that can replace damaged human intestine.”
A scientific leap forward
The organoids were developed from human cells called induced pluripotent stem cells (iPSCs). These are adult cells taken from skin and blood samples and converted into “blank” stem cells that can be stimulated to multiply into any type of tissue. In this case, scientists created the lab conditions that allowed the stem cells to grow into intestinal organoids -- three-dimensional layers of tissue that include the multiple kinds of cells contained in the bowel.
The organoids were then transferred into mice that were genetically engineered so that their immune systems could accept the introduction of human tissues. The grafting procedure, performed under a microscope, placed the organoid under the capsule of the mouse’s kidney to provide a space for blood vessels to form. The study found that the cells grew and multiplied on their own, producing significant amounts of fully functional, fully human intestine.
“The mucosal lining contains all the differentiated cells and continuously renews itself by proliferation of intestinal stem cells. In addition, the mucosa develops both absorptive and digestive ability that was not evident in the culture dish,” Helmrath says. “Importantly, the muscle layers of the intestine also develop.”
What this means for patients
The new findings eventually could be good news for people born with genetic defects affecting their digestive systems or who have lost intestinal function due to necrotizing enterocolitis, cancer, Crohn’s disease and other related inflammatory bowel diseases (IBD).
Success at growing and grafting organoid tissue could transform the field of organ transplantation. If grafted tissue can grow and function properly in the patient, damaged hearts, livers and kidneys might someday be repaired without organ transplants. Repairing brains damaged by Alzheimer’s disease, stroke or injury – where transplantation is not possible -- enters the realm of possibility.
One significant advantage of this method is that the organoid can be grown from the patient’s own tissue, thus eliminating the risk and expense of life-long medications to prevent transplant rejection.
It will take years of further research to bring lab-grown tissue replacement into the mainstream of medical practice. In the meantime, the discovery could have other, more immediate benefits by accelerating drug development and the concept of personalized medicine.
The current process for developing new medications depends on a long and imperfect process of animal testing. Promising compounds from the lab are tested in animals bred to mimic human diseases and conditions. However, many compounds that prove effective and safe in mice turn out to be unsuccessful in human clinical trials. Others have mixed results, where some groups of patients clearly benefit from the new drug, but others suffer harmful side effects.
Lab-grown organoids have the potential to accelerate drug development through bypassing a traditional stage of animal testing and focusing directly upon human tissue. By going straight to human tissue testing, several years might be shaved off the nearly two decades it can take to move a new drug from discovery to market.
Further, this study proves that tissue taken from individual patients could be custom-grown, which means doctors could test and know in advance whether a proposed treatment is likely to work or to cause harmful side effects. “If you know how a patient’s tissue specifically responds to the various available drugs for treating a disease, then you can choose the right drug at the beginning of treatment,” says Helmrath, who also is Surgical Director of the Intestinal Rehabilitation Program at Cincinnati Children’s. “This would benefit patients with many kinds of complex diseases.”
Today’s report represents the latest step in years of stem cell and organoid research at Cincinnati Children’s, much of which has been led by James Wells, PhD, and Noah Shroyer, PhD.
Wells and colleagues first reported success at growing intestinal organoids in the lab in December 2010. Since then, the team has reported similar success at growing organoids of stomach tissue.
“This work is an important advance because it demonstrates that the ‘mini guts’ that we generate from pluripotent stem cells in a petri dish have the potential to form tissue that is virtually indistinguishable from adult intestine,” Wells says. “With this new technology, researchers can now study human intestinal diseases in a way that was not possible before.”
More work is needed to move beyond mouse models and into human clinical trials. “Only after clinical trials demonstrate the safety and effectiveness of stem cell-grown organ tissue will such material be available for those who need transplants,” Helmrath says.
In addition to senior author Helmrath, who also is a Professor in the Department of General Surgery at the University of Cincinnati, the paper in Nature Medicine included 12 co-authors. They include Cincinnati Children’s researchers Wells and Shroyer as well as Carey Watson – who also is a surgical resident in Department of General Surgery, University of Cincinnati – Maxime Mahe, Jorge Múnera, Jonathan Howell, Nambirajan Sundaram, Holly Poling, Jamie Schweitzer, and Jefferson Vallance. Contributing authors from the University of Michigan included Stacy Finkbeiner and Jason Spence.