In a new study led by researchers at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn Medicine) researchers defined key differences in intestinal epithelial cells in patients with Crohn’s disease, a form of inflammatory bowel disease. The findings, which reveal a new epithelial cell state found only in Crohn’s disease, provide key insight into developing prognostic indicators of the disease as well as new avenues for therapies for these diseases. The findings were published today by the journal Cellular and Molecular Gastroenterology and Hepatology.
Crohn’s disease is associated with chronic inflammation within the gastrointestinal tract and sustained damage to the mucosa, a protective layer of epithelium lining the gastrointestinal tract. Epithelial cells maintain the barrier between gut contents and the underlying immune cells, and failure to repair damage to the epithelium is a hallmark of these diseases associated with relapse and need for surgery.
Researchers sought to gain a clearer understanding of epithelial cells in Crohn’s disease at their earliest stages, focusing on stem and progenitor cells. Little is known about how chronic inflammation impacts stem cells or the underlying mechanisms leading to epithelial damage that can cause the disease.
“Our prior work in lab-grown organoids suggest persistent differences in the epithelium in patients with Crohn’s disease, and further studies have demonstrated that stem cells can retain the memory of past damage with negative consequences,” said first study author Tatiana Karakasheva, PhD, Associate Director of the Gastrointestinal Epithelium Modeling Program at CHOP. “Understanding the impact of Crohn’s disease on stem cell differentiation is of significant interest and could help propel new discoveries and better therapies.”
Building upon their prior work, researchers used patient tissues to create colonoids, which are “mini-intestines” grown in a lab using stem cells from a patient’s colon. Single-cell transcriptomic and epigenomic approaches were used on matching tissue specimens to investigate epithelial gene expression and function in healthy children and adults compared with patients with Crohn’s disease.
The study identified an inflammatory secretory progenitor (ISP) cell state found almost exclusively in patients with Crohn’s disease compared with healthy patients. These cells express markers of normal secretory progenitor cells but also express numerous pro-inflammatory genes. While these genes are not expressed in intestinal stem cells, their chromatin – which is responsible for compacting DNA in cells and poising genes for expression – is accessible in Crohn’s disease stem cells. In Crohn’s disease colonoids, the researchers observed sustained ISP gene expression that was further amplified by addition of pro-inflammatory cytokines or pro-inflammatory macrophages, which are also linked to Crohn’s disease.
“This study reports an epigenetic basis for persistent inflammatory cell states in inflammatory bowel disease,” said senior study author Kathryn Hamilton, PhD, Associate Professor of Pediatrics in the Division of Gastroenterology, Hepatology, and Nutrition at Perelman School of Medicine and CHOP and Co-Director of the Gastrointestinal Epithelium Modeling Program at CHOP. “Additional studies will be needed to determine the value of these cells as a therapeutic target, and this could be an important early marker that allows us to predict disease progression and start intervention as early as possible.”
This study was supported by the Gut Cell Atlas Crohn’s Disease Consortium funded by the Leona M. and Harry B. Helmsley Charitable Trust and is supported by a grant from Helmsley to CHOP. The study was also supported by funding from the Lisa Dean Moseley Foundation, CHOP Institutional Development Funds, and National Institutes of Health.
Karakasheva et al, “An epigenetic basis for sustained inflammatory epithelial progenitor cell states in Crohn’s disease.” Cell Mol Gastroenterol Hepatol. Online October 18, 2025. DOI: 10.1016/j.jcmgh.2025.101665.
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In a new study led by researchers at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn Medicine) researchers defined key differences in intestinal epithelial cells in patients with Crohn’s disease, a form of inflammatory bowel disease. The findings, which reveal a new epithelial cell state found only in Crohn’s disease, provide key insight into developing prognostic indicators of the disease as well as new avenues for therapies for these diseases. The findings were published today by the journal Cellular and Molecular Gastroenterology and Hepatology.
Crohn’s disease is associated with chronic inflammation within the gastrointestinal tract and sustained damage to the mucosa, a protective layer of epithelium lining the gastrointestinal tract. Epithelial cells maintain the barrier between gut contents and the underlying immune cells, and failure to repair damage to the epithelium is a hallmark of these diseases associated with relapse and need for surgery.
Researchers sought to gain a clearer understanding of epithelial cells in Crohn’s disease at their earliest stages, focusing on stem and progenitor cells. Little is known about how chronic inflammation impacts stem cells or the underlying mechanisms leading to epithelial damage that can cause the disease.
“Our prior work in lab-grown organoids suggest persistent differences in the epithelium in patients with Crohn’s disease, and further studies have demonstrated that stem cells can retain the memory of past damage with negative consequences,” said first study author Tatiana Karakasheva, PhD, Associate Director of the Gastrointestinal Epithelium Modeling Program at CHOP. “Understanding the impact of Crohn’s disease on stem cell differentiation is of significant interest and could help propel new discoveries and better therapies.”
Building upon their prior work, researchers used patient tissues to create colonoids, which are “mini-intestines” grown in a lab using stem cells from a patient’s colon. Single-cell transcriptomic and epigenomic approaches were used on matching tissue specimens to investigate epithelial gene expression and function in healthy children and adults compared with patients with Crohn’s disease.
The study identified an inflammatory secretory progenitor (ISP) cell state found almost exclusively in patients with Crohn’s disease compared with healthy patients. These cells express markers of normal secretory progenitor cells but also express numerous pro-inflammatory genes. While these genes are not expressed in intestinal stem cells, their chromatin – which is responsible for compacting DNA in cells and poising genes for expression – is accessible in Crohn’s disease stem cells. In Crohn’s disease colonoids, the researchers observed sustained ISP gene expression that was further amplified by addition of pro-inflammatory cytokines or pro-inflammatory macrophages, which are also linked to Crohn’s disease.
“This study reports an epigenetic basis for persistent inflammatory cell states in inflammatory bowel disease,” said senior study author Kathryn Hamilton, PhD, Associate Professor of Pediatrics in the Division of Gastroenterology, Hepatology, and Nutrition at Perelman School of Medicine and CHOP and Co-Director of the Gastrointestinal Epithelium Modeling Program at CHOP. “Additional studies will be needed to determine the value of these cells as a therapeutic target, and this could be an important early marker that allows us to predict disease progression and start intervention as early as possible.”
This study was supported by the Gut Cell Atlas Crohn’s Disease Consortium funded by the Leona M. and Harry B. Helmsley Charitable Trust and is supported by a grant from Helmsley to CHOP. The study was also supported by funding from the Lisa Dean Moseley Foundation, CHOP Institutional Development Funds, and National Institutes of Health.
Karakasheva et al, “An epigenetic basis for sustained inflammatory epithelial progenitor cell states in Crohn’s disease.” Cell Mol Gastroenterol Hepatol. Online October 18, 2025. DOI: 10.1016/j.jcmgh.2025.101665.
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