CHOP Research Unlocks New Insights into Crohn's Disease Mechanisms and Treatments

New Research Sheds Light on Crohn's Disease Epithelial Cells

Researchers from the Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania have made groundbreaking discoveries regarding the role of epithelial cells in Crohn's disease, a complex form of inflammatory bowel disease (IBD). This study uncovers critical variations in intestinal epithelial cells among patients suffering from this persistent condition, offering new avenues for both diagnostic and therapeutic strategies.

Crohn's disease is characterized by chronic inflammation in the gastrointestinal tract, which results in lasting damage to the mucosa—the protective epithelial layer lining the gut. This research aims to enhance the understanding of how epithelial cells function, particularly under the duress of chronic inflammation. Failures in the repair of epithelial damage are indicative of the disease's complications, which often necessitate surgery.

The study delves into the mechanisms impacting stem and progenitor cells, which have not been thoroughly examined in the context of chronic inflammation. Previous research demonstrated that these stem cells may retain a "memory" of past damage, negatively influencing their performance and the overall condition of the intestinal lining. Dr. Tatiana Karakasheva, a leading researcher in the study, highlights the importance of this understanding as a potential catalyst for future advancements in Crohn's disease therapies.

Employing innovative techniques, researchers utilized patient-derived tissues to cultivate colonoids—miniature versions of the intestine that are grown in the lab from stem cells. They conducted detailed analyses using sophisticated genomic approaches to compare the epithelial gene expression and functionality between healthy individuals and those afflicted with Crohn's disease. This meticulous examination revealed a unique inflammatory secretory progenitor (ISP) cell state that is predominantly present in Crohn's patients, absent in healthy subjects. While these ISP cells show normal progenitor cell markers, they also express multiple pro-inflammatory genes.

Significantly, although these pro-inflammatory genes are not found in intestinal stem cells, researchers discovered that the chromatin of Crohn's disease-related stem cells is more accessible. This chromatin accessibility is pivotal for gene expression, leading to persistent ISP gene activation within the colonoids derived from Crohn's patients. The researchers noted that the addition of pro-inflammatory cytokines or macrophages—both connected to Crohn's disease—amplifies this expression further.

Dr. Kathryn Hamilton, the senior author of the study, emphasizes the epigenetic foundations of these persistent inflammatory cell states as a promising area for further exploration. Determining the value of ISPs as a target for therapies could provide a method for early prediction of disease progression, ultimately allowing for timely interventions.

This research, published in the journal Cellular and Molecular Gastroenterology and Hepatology, not only highlights the pivotal differences among epithelial cells in Crohn's patients but also sets the stage for discovering novel prognostic tools and treatment avenues for those affected by the disease. The study was bolstered by generosity from the Gut Cell Atlas Crohn's Disease Consortium, and various other funding sources.

The Children's Hospital of Philadelphia stands at the forefront of pediatric care and research, having been established as the nation's first pediatric hospital in 1855. With a commitment to patient care and research, CHOP seeks to leverage its findings from studies like this to influence practices in treating Crohn's disease and other similar ailments, ensuring better outcomes for pediatric patients everywhere.