title: Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus.
abstract: OBJECTIVE
  The existence of slowly cycling, adult stem cells has been challenged by the identification of actively cycling cells. We investigated the existence of uncommitted, slowly cycling cells by tracking 5-iodo-2'-deoxyuridine (IdU) label-retaining cells (LRCs) in normal esophagus, Barrett's esophagus (BE), esophageal dysplasia, adenocarcinoma, and healthy stomach tissues from patients.
  
  
  METHODS
  Four patients (3 undergoing esophagectomy, 1 undergoing esophageal endoscopic mucosal resection for dysplasia and an esophagectomy for esophageal adenocarcinoma) received intravenous infusion of IdU (200 mg/m(2) body surface area; maximum dose, 400 mg) over a 30-minute period; the IdU had a circulation half-life of 8 hours. Tissues were collected at 7, 11, 29, and 67 days after infusion, from regions of healthy esophagus, BE, dysplasia, adenocarcinoma, and healthy stomach; they were analyzed by in situ hybridization, flow cytometry, and immunohistochemical analyses.
  
  
  RESULTS
  No LRCs were found in dysplasias or adenocarcinomas, but there were significant numbers of LRCs in the base of glands from BE tissue, in the papillae of the basal layer of the esophageal squamous epithelium, and in the neck/isthmus region of healthy stomach. These cells cycled slowly because IdU was retained for at least 67 days and co-labeling with Ki-67 was infrequent. In glands from BE tissues, most cells did not express defensin-5, Muc-2, or chromogranin A, indicating that they were not lineage committed. Some cells labeled for endocrine markers and IdU at 67 days; these cells represented a small population (<0.1%) of epithelial cells at this time point. The epithelial turnover time of the healthy esophageal mucosa was approximately 11 days (twice that of the intestine).
  
  
  CONCLUSIONS
  LRCs of human esophagus and stomach have many features of stem cells (long lived, slow cycling, uncommitted, and multipotent), and can be found in a recognized stem cell niche. Further analyses of these cells, in healthy and metaplastic epithelia, is required.
authors.affiliation: Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
authors.forename: Anna M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: Hugh
authors.initials: H
authors.lastname: Barr
authors.forename: Lea-Anne
authors.initials: LA
authors.lastname: Harrison
authors.forename: George D
authors.initials: GD
authors.lastname: Wilson
authors.forename: Julia
authors.initials: J
authors.lastname: Burkert
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Alison
authors.forename: Leendert
authors.initials: L
authors.lastname: Looijenga
authors.forename: Wey-Ran
authors.initials: WR
authors.lastname: Lin
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harrison
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Jankowski
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002453:Cell Cycle / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D016629:Esophagectomy / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007065:Idoxuridine / Q000494:pharmacology; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008297:Male; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D012016:Reference Values; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D013194:Staining and Labeling; D013270:Stomach / Q000473:pathology*
chemical_list: D007065:Idoxuridine