Cloning and variation of ground state intestinal stem cells

Xia Wang, Yusuke Yamamoto, Lane H. Wilson, Ting Zhang, Brooke E. Howitt, Melissa A. Farrow, Florian Kern, Gang Ning, Yue Hong, Chiea Chuen Khor, Benoit Chevalier, Denis Bertrand, Lingyan Wu, Niranjan Nagarajan, Francisco A. Sylvester, Jeffrey S. Hyams, Thomas Devers, Roderick Bronson, D. Borden Lacy, Khek Yu Ho, Christopher P. Crum, Frank McKeon () and Wa Xian ()
Additional contact information
Xia Wang: The Jackson Laboratory for Genomic Medicine
Yusuke Yamamoto: The Jackson Laboratory for Genomic Medicine
Lane H. Wilson: The Jackson Laboratory for Genomic Medicine
Ting Zhang: Genome Institute of Singapore, Agency for Science, Technology and Research
Brooke E. Howitt: Brigham and Women's Hospital
Melissa A. Farrow: Microbiology, and Immunology, Vanderbilt University School of Medicine
Florian Kern: Genome Institute of Singapore, Agency for Science, Technology and Research
Gang Ning: The Jackson Laboratory for Genomic Medicine
Yue Hong: The Jackson Laboratory for Genomic Medicine
Chiea Chuen Khor: Genome Institute of Singapore, Agency for Science, Technology and Research
Benoit Chevalier: The Jackson Laboratory for Genomic Medicine
Denis Bertrand: Genome Institute of Singapore, Agency for Science, Technology and Research
Lingyan Wu: Genome Institute of Singapore, Agency for Science, Technology and Research
Niranjan Nagarajan: Genome Institute of Singapore, Agency for Science, Technology and Research
Francisco A. Sylvester: The University of North Carolina at Chapel Hill
Jeffrey S. Hyams: Hepatology, and Nutrition, Connecticut Children's Medical Center
Thomas Devers: University of Connecticut Health Center
Roderick Bronson: Harvard Medical School
D. Borden Lacy: Microbiology, and Immunology, Vanderbilt University School of Medicine
Khek Yu Ho: National University of Singapore
Christopher P. Crum: Brigham and Women's Hospital
Frank McKeon: The Jackson Laboratory for Genomic Medicine
Wa Xian: The Jackson Laboratory for Genomic Medicine

Nature, 2015, vol. 522, issue 7555, 173-178

Abstract: Abstract Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, ‘ground state’ stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine.

Date: 2015
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DOI: 10.1038/nature14484

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