Intestinal Epithelial Stem Cells and Progenitors

Bjerknes, Matthew; Cheng, Hazel

doi:10.1016/s0076-6879(06)19014-x

Cited by 100 publications

(88 citation statements)

References 189 publications

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“…Finally, Wnt signaling is required to maintain the self-renewal capacity of stem cells (24,25,41). The identity and location of intestinal epithelial stem cells remain unclear, due to the lack of clonogenic assays for validating candidate markers (42). Although our study does not definitively identify the small intestinal stem cells, our findings raise interesting questions as to their identity and how they respond to stress.…”

Section: Discussionmentioning

confidence: 79%

Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion

Lee¹,

White

Hurov

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The CDC25 protein phosphatases (CDC25A, B, and C) drive cell cycle transitions by activating key components of the cell cycle engine. CDC25A and CDC25B are frequently overproduced in human cancers. Disruption of Cdc25B or Cdc25C individually or in combination has no effect on mouse viability. Here we report that CDC25A is the only family member to provide an essential function during early embryonic development, and that other family members compensate for its loss in adult mice. In contrast, conditional disruption of the entire family is lethal in adults due to a loss of small intestinal epithelial cell proliferation in crypts of Lieberkü hn. Cdc25 loss induced Wnt signaling, and overall crypt structures were preserved. In the face of continuous Wnt signaling, nearly all crypt epithelial progenitors differentiated into multiple cell lineages, including crypt base columnar cells, a proposed stem cell. A small population of Musashi/Dcamkl-1/nuclear ␤-catenin-positive epithelial cells was retained in these crypts. These findings have implications for the development of novel, less cytotoxic cancer chemotherapeutic drugs that specifically target the cell cycle.CDC25 phosphatases ͉ cell cycle ͉ stem cells T he CDC25 phosphatases promote cell cycle progression by activating cyclin-dependent protein kinases (1-6). In mice, Cdc25A, B, and C exhibit overlapping but distinct patterns of expression during development and in adult tissues (7-10). This suggests that they have distinct biological functions in embryonic and adult mice. Mice lacking CDC25B and CDC25C, individually or in combination, are viable and develop normally, and embryonic fibroblasts derived from these mice exhibit normal cell cycle parameters in culture (11-13). These findings demonstrate that mice can survive throughout embryogenesis and adulthood with a single member of the family, CDC25A. Here we report the consequences of deleting Cdc25A alone and in combination with Cdc25B and Cdc25C in mice. Our data demonstrate that CDC25A provides an essential function during early embryogenesis, and that CDC25B and/or CDC25C compensate for CDC25A loss in adult mice. In contrast, mice lacking all 3 CDC25s die within 1 week due to complete loss of epithelial cell proliferation in the small intestinal crypts.We used this model to explore how small intestine stem and progenitor cells respond to the acute disruption of cell division. The self-renewing epithelium of the adult small intestine contains tetrapotent stem cells that give rise to rapidly proliferating committed daughter cells, which in turn produce terminally differentiated cells (14). One of these lineages, Paneth cells, are located in crypts of Lieberkühn along with stem and progenitor cells. Analysis of gene expression and cellular morphology, as well as lineage tracing experiments, suggest that stem cells are intermingled with or lie just above Paneth cells at the crypt base (15-18). These stem cells are considered to provide the source of recovery after damage to the epithelial lining from such facto...

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Section: Discussionmentioning

confidence: 79%

Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion

Lee¹,

White

Hurov

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…We explored AGR2 expression in the normal mouse small intestine because Barrett's esophagus is characterized by intestinal metaplasia, which significantly increases the risk of developing adenocarcinoma. In addition, knowledge available with respect to intestinal development and cell growth may be capitalized to provide insights into AGR2's function in normal gastrointestinal cells and tumors (25,26). The small intestine is composed of four cell types, absorptive enterocytes, goblet cells, Paneth cells, and enteroendocrine cells; with the latter three classified together as secretory cells.…”

Section: Resultsmentioning

confidence: 99%

The Adenocarcinoma-Associated Antigen, AGR2, Promotes Tumor Growth, Cell Migration, and Cellular Transformation

2008

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The AGR2 gene encodes a secretory protein that is highly expressed in adenocarcinomas of the esophagus, pancreas, breast, and prostate. This study explores the effect of AGR2 expression with well-established in vitro and in vivo assays that screen for cellular transformation and tumor growth. AGR2 expression in SEG-1 esophageal adenocarcinoma cells was reduced with RNA interference. Cellular transformation was examined using NIH3T3 cells that express AGR2 after stable transfection. The cell lines were studied in vitro with assays for density-dependent and anchorage-independent growth, and in vivo as tumor xenografts in nude mice. SEG-1 cells with reduced AGR2 expression showed an 82% decrease in anchorage-independent colony growth and a 60% reduction in tumor xenograft size. In vitro assays of AGR2-expressing NIH3T3 cells displayed enhanced foci formation and anchorage-independent growth. In vivo, AGR2-expressing NIH3T3 cells established tumors in nude mice. Thus, AGR2 expression promotes tumor growth in esophageal adenocarcinoma cells and is able to transform NIH3T3 cells. Immunohistochemistry of the normal mouse intestine detected AGR2 expression in proliferating and differentiated intestinal cells of secretory lineage. AGR2 may be important for the growth and development of the intestine as well as esophageal adenocarcinomas. [Cancer Res 2008;68(2):492-7]

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“…To identify cells initially labeled by Bmi1 expression, it is important to analyze expression of the LacZ reporter as early as possible after tamoxifen injection. The primary location of ISCs-between Paneth cells 21 or above them 19 -has been a matter of some debate. To assess the position of Bmi1-expressing cells early after tamoxifen induction, we harvested small intestines from Bmi1 Cre-ER/+ ;Rosa26 LacZ/+ mice at different time points, stained them for LacZ activity and sectioned them.…”

mentioning

confidence: 99%

Bmi1 is expressed in vivo in intestinal stem cells

2008

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Bmi1 plays an essential part in the self-renewal of hematopoietic and neural stem cells. To investigate its role in other adult stem cell populations, we generated a mouse expressing a tamoxifen-inducible Cre from the Bmi1 locus. We found that Bmi1 is expressed in discrete cells located near the bottom of crypts in the small intestine, predominantly four cells above the base of the crypt (+4 position). Over time, these cells proliferate, expand, self-renew and give rise to all the differentiated cell lineages of the small intestine epithelium. The induction of a stable form of b-catenin in these cells was sufficient to rapidly generate adenomas. Moreover, ablation of Bmi1 + cells using a Rosa26 conditional allele, expressing diphtheria toxin, led to crypt loss. These experiments identify Bmi1 as an intestinal stem cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing stem cells along the length of the small intestine suggested that mammals use more than one molecularly distinguishable adult stem cell subpopulation to maintain organ homeostasis.Adult somatic stem cells are defined by two major properties: the ability to generate more stem cells (self-renewal) and the ability to generate differentiated cell lineages 1 . To establish the presence of these two properties, the gold standard is to assess both of them in vivo and in vitro 2 . Several studies have shown in vitro that many tissues carry cells capable of selfrenewal and of giving rise to differentiated cell types. However, few experiments have clearly established in vivo self-renewal and multipotency of these cells over time 3,4 .To address this, we established a genetic fate-mapping system for stem cell populations in vivo. We chose as our target locus Bmi1, a gene already known to be involved in the selfrenewal of neuronal, hematopoietic and leukemic cells [5][6][7] . Bmi1 was first identified in a mouse proviral insertion screen for lymphomagenesis 8 . It is part of the Polycomb group gene family, and specifically a member of polycomb-repressing complex 1 (PRC1). PRC1 has an essential role in maintaining chromatin silencing 9, 10. Bmi1 −/− mice die before or near weaning from a defect in self-renewal of hematopoietic stem cells 11,12 . Our hypothesis was that PRC1 might be part of a general mechanism for maintaining self-renewal in various adult stem cell populations.We inserted a construct encoding a internal ribosome entry site (IRES)-Cre-estrogen receptor binding domain fusion (IRES-Cre-ER) into the 3′ untranslated region of Bmi1 ( Supplementary Fig. 1 To evaluate the repopulation kinetics of the crypt cells derived from Bmi1 + parents, we analyzed the small intestines of Bmi1 Cre-ER/+ ;Rosa26 LacZ/+ mice from day 2 to day 30 after tamoxifen induction, analyzing and following crypts on serial adjacent sections. Crypts with LacZ + cells presented a large variation in the number of stained cells. From day 2 to day 30, there was a continual increase in the number of cells labeled per crypt . Over time, the number of crypts th...

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Intestinal Epithelial Stem Cells and Progenitors

Cited by 100 publications

References 189 publications

Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion

Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion

The Adenocarcinoma-Associated Antigen, AGR2, Promotes Tumor Growth, Cell Migration, and Cellular Transformation

Bmi1 is expressed in vivo in intestinal stem cells

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