The researchers have developed a novel, patient derived, model of ulcerative colitis, which will help advance studies into new treatments for the chronic inflammatory bowel disease.
The study conducted by researchers from Cleveland Clinic's Lerner Research Institute is published in the journal Nature Communications.
The researchers used this model to identify a promising target that could be blocked to slow the disease progression. Ulcerative colitis occurs due to abnormal reactions of the immune system that lead to inflammation and ulcers on the inner lining of the large intestines. The condition is highly heterogeneous both in terms of patients' symptoms and disease pathology.
Research has suggested that both the immune system and the ulcerative colitis microenvironment (the surrounding, less diseased cellular components) interact to drive disease development and progression.
As the immune-suppressing drugs have demonstrated limited success in treating ulcerative colitis, the researchers are studying whether targeting elements of the microenvironment—which include components of the intestinal lining (called the epithelium) and stem cell-like cells called stromal cells--may be a better or complementary treatment approach.
Lead author of the study Emina Huang, MD, staff in the Departments of Cancer Biology and Colorectal Surgery said, "Gaining a more comprehensive understanding of the complex interplay between immune and other cell types will be critical to developing new and more effective ulcerative colitis therapies and tailored, patient-specific treatment approaches."
Dr. Huang and her team developed their model using tissue samples from patients with ulcerative colitis who underwent surgery at Cleveland Clinic. They isolated fibroblasts cells that can be reprogrammed to develop into all-purpose, undifferentiated cells called induced pluripotent stem cells.
For the study, the researchers grew the stem cells in the lab into tiny, three-dimensional tissues that mimic actual organs (called organoids). The diseased organoids reflected histological and functional features commonly observed in ulcerative colitis patients including reduced mucus secretions, faulty barrier integrity of the intestinal lining and over expression of select proteins (including one called CXCL8).
The team was able to rapidly identify novel drug targets and candidates. By blocking CXCL8 expression with a small molecule called repertaxin slowed the disease progression.
Dr. Huang said, "We look forward to further exploring repertaxin's potential benefit in other preclinical and eventual clinical studies. We are hopeful that others will also find this model useful in identifying other potential anti-ulcerative colitis drugs."
This approach used to develop the new ulcerative colitis model can also be used to model other complex diseases.