Intestinal Stem Cell Replacement Follows a Pattern of Neutral Drift

López‐García, Carlos; Klein, Allon M.; Simons, Benjamin D.; Winton, Douglas J.

doi:10.1126/science.1196236

Cited by 571 publications

(651 citation statements)

References 22 publications

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“…Both would be long lived, give rise to each other, insuring the constancy of the population by a sophisticated retrocontrol (that is, reversible phenotypes; Li and Clevers, 2010). Such a dynamic equilibrium between stem cells has also been demonstrated in intestinal crypts (Lopez-Garcia et al, 2010;Snippert et al, 2010).…”

Section: Csc-tpc Quiescent or Proliferative?mentioning

confidence: 99%

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

Floor¹,

Staveren²,

et al. 2011

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Section: Csc-tpc Quiescent or Proliferative?mentioning

confidence: 99%

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

Floor¹,

Staveren²,

et al. 2011

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“…Specific localization of human leucine-rich repeat containing G protein 5 (LGR5) mRNA was accomplished by in situ hybridization using an antisense riboprobe synthesized with SP6 RNA polymerase using 35 S-UTP and appropriate tissue and experimental controls as previously described. 25 7…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Identification of Lineage-Uncommitted, Long-Lived, Label-Retaining Cells in Healthy Human Esophagus and Stomach, and in Metaplastic Esophagus

et al. 2013

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Background & Aims: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 per m 2 body surface area, maximum dose of 400 mg) over a 30-min period; the IdU had a circulation t 1/2 of 8hs. Tissues were collected at 7, 11, 29 and 67 days following 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 timepoint. 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.4

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“…Elegant work by the Winton and Clevers groups has shown that murine intestinal stem cells form an equipotent population that undergoes stochastic clone extinction, compensated by expansion and replacement by a neighbouring cell. This random enlargement and contraction of clones, known as neutral drift dynamics, can lead to stochastic clonal extinction or niche succession, where one clone expands to fill the entire niche 31, 32. Similar neutral drift dynamics are seen in human colon using mtDNA mutations as clonal markers 33.…”

Section: Stem Cell Dynamics In Homeostasismentioning

confidence: 91%

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

Biswas

Belnoue-Davis

Irshad

et al. 2015

The Journal of Pathology

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The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt–luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies. © 2015 Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Intestinal Stem Cell Replacement Follows a Pattern of Neutral Drift

Cited by 571 publications

References 22 publications

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

Identification of Lineage-Uncommitted, Long-Lived, Label-Retaining Cells in Healthy Human Esophagus and Stomach, and in Metaplastic Esophagus

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

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