Cincinnati Children's researchers have achieved a significant milestone in regenerative medicine by repairing damaged intestines in a rodent model using human pluripotent stem cell (hPSC)-derived organoids. This breakthrough brings decades of research closer to first-in-human clinical trials, offering potential new treatments for conditions such as Crohn's disease and ulcerative colitis.
Intestinal Repair with hPSC-Derived Organoids
In a 2019 observation that foreshadowed this achievement, Holly Poling, Institutional Investigator at the Center for Stem Cell and Organoid Medicine (CuSTOM) at Cincinnati Children’s, witnessed microscopic evidence of human tissue-derived organoids restoring function to a severely damaged loop of rodent intestine. The newly published study expands on this initial finding, detailing the extent and nature of the repair process.
"Our cellular product was much more than a surface patch over intestinal damage," explained Poling, the lead author of the study. "We could see that the cells we introduced induced repairs across all the important layers of the intestine, including the musculature of the mesenchyme and the internal protective surface layer, or epithelium."
The researchers confirmed the formation of various human cell types, including new blood vessels, within the repaired regions. These areas also exhibited appropriate barrier function, responding correctly to chemical stimuli. Importantly, the team found no evidence of human cells migrating to other organs, such as the brain, kidneys, heart, lungs, or liver, during the tracking period.
Development of the Rodent Model
To assess the organoids' ability to repair real organs, the researchers developed a sustainable rodent model. This required two years of gene editing, advanced microsurgery techniques, and veterinary expertise, led by Nambirajan Sundaram, Staff Scientist at CuSTOM, and Alexander Cortez, a former surgical resident.
The team chose a rat model over a mouse model due to the need for a larger animal to reliably perform a "Roux-en-Y" surgical procedure. The rodents, obtained from collaborators in France, were engineered to have partially suppressed immune systems to prevent rejection of human genes and tissues while remaining healthy enough to undergo and recover from surgery.
"Without their full immune system, these rodents often don’t survive very well even without doing any surgery," Sundaram noted. "Ultimately, we were able to standardize our process so that we could track the rodents for 10 weeks after they received the cell therapy. Once the data started coming in, it was very promising."
Implications and Future Directions
The CuSTOM Accelerator Lab is now positioned to conduct further tests to validate the safety of the materials and methods for human clinical studies. This work builds upon Cincinnati Children’s history of organoid development, including the world’s first functional, three-dimensional (3D) intestinal organoid from induced pluripotent stem cells (iPSCs), described in a 2010 Nature study by James Wells.
Magdelena Kasendra, Director of Research and Development at CuSTOM, emphasized the potential of this approach: "There is no other stem cell therapy product with such extensive regenerative potential. Demonstrating its efficacy in the appropriate preclinical model, along with rigorous safety assessments, is a pivotal step toward advancing it to first-in-human clinical trials."
With a patent application in process, Cincinnati Children's is poised to advance this technology toward clinical application, offering hope for patients with debilitating intestinal disorders.
