Lab-grown human tissue effectively repairs damaged intestines in rodent model. The achievement, led by experts at Cincinnati Children’s, brings a multi-year research effort closer to the first human clinical trial. The potential benefits include new therapies for ulcerative colitis, Crohn’s disease and more.
CINCINNAT, September 12, 2024 /PRNewswire/ — There wasn’t one big “Eureka!” moment in this science story; there were many, spanning more than 15 years.
One of those moments came in 2019 when Holly Polingresearcher at Cincinnati Children’s Hospital, has observed microscopic evidence that organoids – once a theory and a distant possibility – actually restore function to a small loop of severely damaged intestine.
Using a rodent model containing human tissue, experts at Cincinnati Children’s have become the first research team in the world to successfully repair damaged intestines using cell therapy based on lab-grown organoid tissue. With the involvement of human cells, the repaired intestine (right) also thickened. The detailed results were published online September 12, 2024, in the journal Cell Stem Cell.
An advanced cell therapy product developed by experts at Cincinnati Children’s appears to outperform another method that stimulates growth of only the superficial layer of the intestinal epithelium. The middle column of images shows the extent of new cell growth in light green. The right column shows the repaired tissue, with organoid cells in brown. Details of the new cell therapy were published September 12, 2024, in Cell Stem Cell.
The repair took place in a rodent, but human tissues were involved.
Now, in a study published online September 12, 2024IN Stem cell Stem cellA team of experts from Cincinnati Children’s Hospital details a breakthrough in the new field of organoid medicine.
“Our cell product did more than just patch up superficial damage to the gut. We saw that the cells we introduced induced repair in all the important layers of the gut, including the muscle mesenchyme and the inner protective surface layer, the epithelium,” Poling says. “We confirmed the formation of different cell types, and all of them were human, including the incorporation of new blood vessels. The repaired areas also showed adequate barrier function. We saw that the cells were responding to the chemicals in the way they should.”
The team also made another discovery that is considered key in the context of trying to perform such repairs in patients:
“We looked at the brain, kidneys, heart, lungs, liver and other areas. During the period we tracked, we didn’t find any human cells in places they shouldn’t be.”
Coming soon: Applying for FDA approval to start clinical trial
Poling is the lead author of the collaborative study, which includes several pioneers in organoid development at Cincinnati Children’s. Michael HelmrathMD, is the corresponding author. Co-authors who have been deeply involved in previous organoid advances at Cincinnati Children’s include Nambirajan SundaramDr. Magdalena Kasendra, Ph.D., Christopher MayhewDoctorate, Maxim MaheDoctorate, Takanori TakebeMD, Doctor of Science and James WellsDoctorate.
Wells was the principal investigator who created the world’s first functional, three-dimensional intestinal organoid from induced pluripotent stem cells, described in a 2010 study Nature.
In the years that followed, Cincinnati Children’s created the Center for Stem Cell & Organoid Medicine (CuSTOM), recruited even more distinguished scientists, and published a series of successes in developing miniature versions of the stomach, esophagus, colon, liver, pancreas, kidneys, lungs, and more. Here, experts grow organoids to mimic the function of blood vessels, brain organoids to study the formation of neurons, and more.
To date, new tissues have been used primarily as test platforms in basic research aimed at understanding the causes and mechanisms of disease and evaluating potential new drugs using small but functional fragments of living human tissue, rather than relying so heavily on animal models.
As gut organoids become more advanced — new versions include functioning nerves, immune cells, and other important features — the possibilities of using them as a form of cell therapy transplant are becoming more realistic.
To support this initiative, Cincinnati Children’s has invested more than 10 million dollars as part of the Pursuing Our Potential Together initiative, which aims to support Helmrath and colleagues in conducting numerous experiments to demonstrate that organoids have the immediate potential to repair damaged human organs.
This investment was supplemented by three grants with a total value 11 million dollars from the Farmer Family Foundation. These gifts helped launch the CuSTOM Accelerator Lab, led by Kasendra, which is spearheading the complex effort to produce organoids that meet the rigorous Good Manufacturing Practice (GMP) standards required for human tissue use.
To achieve this milestone, 35 laboratories from 15 locations at Cincinnati Children’s Hospital were engaged.
“This work represents a huge commitment across the institution,” Helmrath says. “The institution is confident that Cincinnati Children’s will be a world leader in developing and delivering organoid cell therapies.”
Important rodent model
After achieving numerous successes with tiny organoids grown in lab dishes, the research team needed to conduct animal tests to determine whether the new tissues could repair real organs.
It took about two years of innovative gene editing, advanced microsurgical techniques, and excellent veterinary skills to develop a sustainable rodent model for this study. Much of this effort was led by Sundaram and then-surgical resident Alexander Cortezdoctor.
For this line of research, the team focused on a rat model rather than a mouse model because the animal needed to be large enough to reliably perform the “Roux-en-Y” surgical procedure. The surgery essentially creates an extra side loop of intestine in which they could create a tissue lesion and then test how well the new cell therapy repairs the damage. All while the intestine continues to function and process the nutrients passing through it.
The crew began work with a line of rodents provided by co-workers FranceThese rodents were engineered to weaken enough of their immune systems to prevent rejection of implanted human genes and tissues, while still being healthy enough to undergo and recover from surgery.
“Without a full immune system, these rodents often don’t survive very well, even without surgery,” Sundaram says. “Eventually, we were able to standardize our process so that we could follow the rodents for 10 weeks after receiving cell therapy. When the data started coming in, it was very promising.”
Human Research Platform
With a proven rodent model in place, the CuSTOM Accelerator lab can now begin a series of tests that will confirm the safety of the materials and methods that will be used in human clinical trials.
“There is no other stem cell therapy product with such broad regenerative potential. Demonstrating its efficacy in an appropriate preclinical model, along with rigorous safety assessments, is a critical step toward advancing it to first-in-human clinical trials,” Kasendra says.
About this study
In addition to the co-authors listed above, the study also included: Garrett FisherAkaljot Singh, Joseph Shiley, Kalpana NattamaiVinothini Govindarajah, Alexander CortezAND Maksym KrutkoThe collaborators also included Séverine Ménoret and Ignatius Anegon University of Nantes in France.
Funding sources included grants from the National Institutes of Health (U01DK103117 and P30DK078292), the National Science Foundation, the Cincinnati Center for Digestive Health, and the Farmer Family Foundation.
Cincinnati Children’s Hospital is pending a patent application related to the research work.
Learn more
Learn more about organoid research at Cincinnati Children’s
How Philanthropists Can Support Organoid Research
Learn more about careers in organoid research
SOURCE Cincinnati Children’s Hospital Medical Center
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