Carl Grim1,2, Robert Noble3, Gabriela Uribe1,2,3, Kamil Khanipov4, Paul Johnson2,4, Walter A Koltun5, Tammara Watts2,6, Yuriy Fofanov4, Gregory S Yochum7, Don W Powell1,2, Ellen J Beswick8, Irina V Pinchuk2,3. 1. Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA. 2. Institute of Translational Science, University of Texas Medical Branch, Galveston, TX, USA. 3. Department of Medicine, PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA. 4. Department of Pharmacology & Toxicology, at the University of Texas Medical Branch, Galveston, TX, USA. 5. Department of Colorectal Surgery, PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA. 6. Department of Head and Neck Surgery and Communication Sciences, Duke University School of Medicine, Durham, NC, USA. 7. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA. 8. Department of Biochemistry and Molecular Biology, PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA.
Abstract
BACKGROUND AND AIMS: Little is known about the presence and function of tissue-resident mesenchymal stem cells [MtSCs] within the gastrointestinal mucosa in health and inflammatory bowel disease [IBD]. The contribution of MtSCs to the generation of inflammatory fibroblasts during IBD is also poorly understood. We hypothesized that IBD-MtSCs are impaired and contribute to the generation of the pathological myofibroblasts in IBD. METHODS: In a cohort of clinically and endoscopically active IBD patients and normal controls, we used quantitative RT-PCR and stem cell differentiation assays, as well as confocal microscopy, to characterize MtSCs. RESULTS: Expression of two stem cell markers, Oct4 and ALDH1A, was increased in the inflamed IBD colonic mucosa and correlated with an increase of the mesenchymal lineage marker Grem1 in ulcerative colitis [UC], but not Crohn's disease [CD]. Increased proliferation and aberrant differentiation of Oct4+Grem1+ MtSC-like cells was observed in UC, but not in CD colonic mucosa. In contrast to normal and UC-derived MtSCs, CD-MtSCs lose their clonogenic and most of their differentiation capacities. Our data also suggest that severe damage to these cells in CD may account for the pathological PD-L1low phenotype of CD myofibroblasts. In contrast, aberrant differentiation of MtSCs appears to be involved in the appearance of pathological partially differentiated PD-L1high myofibroblasts within the inflammed colonic mucosa in UC. CONCLUSION: Our data show, for the first time, that the progenitor functions of MtSCs are differentially impaired in CD vs UC, providing a scientific rationale for the use of allogeneic MSC therapy in IBD, and particularly in CD. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation (ECCO) 2021.
BACKGROUND AND AIMS: Little is known about the presence and function of tissue-resident mesenchymal stem cells [MtSCs] within the gastrointestinal mucosa in health and inflammatory bowel disease [IBD]. The contribution of MtSCs to the generation of inflammatory fibroblasts during IBD is also poorly understood. We hypothesized that IBD-MtSCs are impaired and contribute to the generation of the pathological myofibroblasts in IBD. METHODS: In a cohort of clinically and endoscopically active IBD patients and normal controls, we used quantitative RT-PCR and stem cell differentiation assays, as well as confocal microscopy, to characterize MtSCs. RESULTS: Expression of two stem cell markers, Oct4 and ALDH1A, was increased in the inflamed IBD colonic mucosa and correlated with an increase of the mesenchymal lineage marker Grem1 in ulcerative colitis [UC], but not Crohn's disease [CD]. Increased proliferation and aberrant differentiation of Oct4+Grem1+ MtSC-like cells was observed in UC, but not in CD colonic mucosa. In contrast to normal and UC-derived MtSCs, CD-MtSCs lose their clonogenic and most of their differentiation capacities. Our data also suggest that severe damage to these cells in CD may account for the pathological PD-L1low phenotype of CD myofibroblasts. In contrast, aberrant differentiation of MtSCs appears to be involved in the appearance of pathological partially differentiated PD-L1high myofibroblasts within the inflammed colonic mucosa in UC. CONCLUSION: Our data show, for the first time, that the progenitor functions of MtSCs are differentially impaired in CD vs UC, providing a scientific rationale for the use of allogeneic MSC therapy in IBD, and particularly in CD. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation (ECCO) 2021.
Authors: Daniel L Worthley; Michael Churchill; Jocelyn T Compton; Yagnesh Tailor; Meenakshi Rao; Yiling Si; Daniel Levin; Matthew G Schwartz; Aysu Uygur; Yoku Hayakawa; Stefanie Gross; Bernhard W Renz; Wanda Setlik; Ashley N Martinez; Xiaowei Chen; Saqib Nizami; Heon Goo Lee; H Paco Kang; Jon-Michael Caldwell; Samuel Asfaha; C Benedikt Westphalen; Trevor Graham; Guangchun Jin; Karan Nagar; Hongshan Wang; Mazen A Kheirbek; Alka Kolhe; Jared Carpenter; Mark Glaire; Abhinav Nair; Simon Renders; Nicholas Manieri; Sureshkumar Muthupalani; James G Fox; Maximilian Reichert; Andrew S Giraud; Robert F Schwabe; Jean-Phillipe Pradere; Katherine Walton; Ajay Prakash; Deborah Gumucio; Anil K Rustgi; Thaddeus S Stappenbeck; Richard A Friedman; Michael D Gershon; Peter Sims; Tracy Grikscheit; Francis Y Lee; Gerard Karsenty; Siddhartha Mukherjee; Timothy C Wang Journal: Cell Date: 2015-01-15 Impact factor: 41.582
Authors: Ellen J Beswick; Carl Grim; Abinav Singh; Jose E Aguirre; Marissa Tafoya; Suimin Qiu; Gerhard Rogler; Rohini McKee; Von Samedi; Thomas Y Ma; Victor E Reyes; Don W Powell; Irina V Pinchuk Journal: Front Immunol Date: 2018-05-30 Impact factor: 7.561