Cloning and variation of ground state intestinal stem cells

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacterial Toxins / pharmacology
  • Cell Differentiation / drug effects
  • Cell Lineage
  • Cells, Cultured
  • Clone Cells / cytology
  • Clone Cells / metabolism
  • Clostridioides difficile / physiology
  • Colon / cytology
  • Colon / drug effects
  • Enterocolitis, Pseudomembranous / microbiology
  • Enterocolitis, Pseudomembranous / pathology
  • Epigenesis, Genetic / genetics
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Fetus / cytology
  • Genomic Instability / genetics
  • Humans
  • Intestine, Small / cytology
  • Intestines / cytology*
  • Intestines / drug effects
  • Organoids / cytology
  • Organoids / growth & development
  • Stem Cells / cytology*
  • Stem Cells / metabolism*


  • Bacterial Toxins
  • Clostridium difficile lethal toxin B

Associated data

  • GEO/GSE66749