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Nature. 2015 Jun 11;522(7555):173-8. doi: 10.1038/nature14484. Epub 2015 Jun 3.

Cloning and variation of ground state intestinal stem cells.

Author information

1
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
2
1] The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA [2] Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
3
Genome Institute of Singapore, Agency for Science, Technology and Research, 138672 Singapore.
4
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02118, USA.
5
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
6
1] Genome Institute of Singapore, Agency for Science, Technology and Research, 138672 Singapore [2] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore.
7
Department of Pediatrics, Division of Gastroenterology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
8
Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut 06106, USA.
9
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
10
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
11
Department of Medicine, National University of Singapore, 119228 Singapore.
12
1] The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA [2] Genome Institute of Singapore, Agency for Science, Technology and Research, 138672 Singapore [3] Department of Medicine, National University of Singapore, 119228 Singapore [4] Multiclonal Therapeutics, Inc., Farmington, Connecticut 06032, USA.
13
1] The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA [2] Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06032, USA [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02118, USA [4] Department of Medicine, National University of Singapore, 119228 Singapore [5] Multiclonal Therapeutics, Inc., Farmington, Connecticut 06032, USA.

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.

PMID:
26040716
PMCID:
PMC4853906
DOI:
10.1038/nature14484
[Indexed for MEDLINE]
Free PMC Article
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