Cambrian Y Liu1, Nandini Girish2, Marie L Gomez3, Philip E Dubé4, M Kay Washington5, Benjamin D Simons6, D Brent Polk7. 1. Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Medicine, The University of Chicago, Chicago, Illinois. 2. Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California. 3. Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California. 4. Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California. 5. Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee. 6. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom. 7. Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California; Department of Pediatrics, Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California. Electronic address: dpolk@ucsd.edu.
Abstract
BACKGROUND & AIMS: Epithelial wound healing is compromised and represents an unleveraged therapeutic target in inflammatory bowel disease (IBD). Intestinal epithelial cells exhibit plasticity that facilitates dedifferentiation and repair during the response to injury. However, it is not known whether epithelial cells of a neighboring organ can be activated to mediate re-epithelialization in acute colitis. Histological findings of a permanent squamous tissue structure in the distal colon in human IBD could suggest diverse cellular origins of repair-associated epithelium. Here, we tested whether skin-like cells from the anus mediate colonic re-epithelialization in murine colitis. METHODS: We studied dextran sulfate sodium-induced colitis and interleukin 10-deficient colitis in transgenic mice. We performed lineage tracing, 3-dimensional (3D) imaging, single-cell transcriptomics, and biophysical modeling to map squamous cell fates and to identify squamous cell types involved in colonic repair. RESULTS: In acute and chronic colitis, we found a large squamous epithelium, called squamous neo-epithelium of the colon (SNEC), near the anorectal junction. Neighboring squamous cells of the anus rapidly migrate into the ulcerated colon and establish this permanent epithelium of crypt-like morphology. These squamous cells derive from a small unique transition zone, distal to the border of colonic and anal epithelium, that resists colitic injury. The cells of this zone have a pre-loaded program of colonic differentiation and further upregulate key aspects of colonic epithelium during repair. CONCLUSION: Transitional anal cells represent unique reserve cells capable of rebuilding epithelial structures in the colon after colitis. Further study of these cells could reveal novel approaches to direct mucosal healing in inflammation and disease.
BACKGROUND & AIMS: Epithelial wound healing is compromised and represents an unleveraged therapeutic target in inflammatory bowel disease (IBD). Intestinal epithelial cells exhibit plasticity that facilitates dedifferentiation and repair during the response to injury. However, it is not known whether epithelial cells of a neighboring organ can be activated to mediate re-epithelialization in acute colitis. Histological findings of a permanent squamous tissue structure in the distal colon in human IBD could suggest diverse cellular origins of repair-associated epithelium. Here, we tested whether skin-like cells from the anus mediate colonic re-epithelialization in murine colitis. METHODS: We studied dextran sulfate sodium-induced colitis and interleukin 10-deficient colitis in transgenic mice. We performed lineage tracing, 3-dimensional (3D) imaging, single-cell transcriptomics, and biophysical modeling to map squamous cell fates and to identify squamous cell types involved in colonic repair. RESULTS: In acute and chronic colitis, we found a large squamous epithelium, called squamous neo-epithelium of the colon (SNEC), near the anorectal junction. Neighboring squamous cells of the anus rapidly migrate into the ulcerated colon and establish this permanent epithelium of crypt-like morphology. These squamous cells derive from a small unique transition zone, distal to the border of colonic and anal epithelium, that resists colitic injury. The cells of this zone have a pre-loaded program of colonic differentiation and further upregulate key aspects of colonic epithelium during repair. CONCLUSION: Transitional anal cells represent unique reserve cells capable of rebuilding epithelial structures in the colon after colitis. Further study of these cells could reveal novel approaches to direct mucosal healing in inflammation and disease.
Authors: Philip E Dubé; Fang Yan; Shivesh Punit; Nandini Girish; Steven J McElroy; M Kay Washington; D Brent Polk Journal: J Clin Invest Date: 2012-07-09 Impact factor: 14.808