title: Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas.
abstract: Lineage-tracing approaches, widely used to characterize stem cell populations, rely on the specificity and stability of individual markers for accurate results. We present a method in which genetic labeling in the intestinal epithelium is acquired as a mutation-induced clonal mark during DNA replication. By determining the rate of mutation in vivo and combining this data with the known neutral-drift dynamics that describe intestinal stem cell replacement, we quantify the number of functional stem cells in crypts and adenomas. Contrary to previous reports, we find that significantly lower numbers of "working" stem cells are present in the intestinal epithelium (five to seven per crypt) and in adenomas (nine per gland), and that those stem cells are also replaced at a significantly lower rate. These findings suggest that the bulk of tumor stem cell divisions serve only to replace stem cell loss, with rare clonal victors driving gland repopulation and tumor growth.
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kozar
authors.forename: Edward
authors.initials: E
authors.lastname: Morrissey
authors.forename: Anna M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: Maartje
authors.initials: M
authors.lastname: van der Heijden
authors.forename: Heather I
authors.initials: HI
authors.lastname: Zecchini
authors.forename: Richard
authors.initials: R
authors.lastname: Kemp
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.forename: Louis
authors.initials: L
authors.lastname: Vermeulen
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Winton
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*