Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration

Barker, Nick

doi:10.1038/nrm3721

Cited by 1,042 publications

(1,054 citation statements)

References 121 publications

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“…As the ISC compartment is maintained by Wnt and Notch signals, 1 we tested the effects of the ligands Wnt3a and Jagged1, which are known to activate the Wnt and Notch pathways in organotypic culture. 33 We found that Wnt3a, but not ); GDC: GDC0941 500 nM).…”

Section: Above)mentioning

confidence: 99%

“…These in turn differentiate into enterocytes and secretory cell types. 1 Cellular hierarchies are gradually modified during intestinal tumor initiation and progression by mutations in signaling pathways controlling homeostasis. Consequently, colon cancers can therefore exhibit gene activity characteristic for different intestinal cell types and colon cancer subtypes defined by such expression patterns differ in their therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 In the normal intestine, Wnt signals are emitted in the crypt base by secretory Paneth cells and myofibroblasts and received by ISCs and in an autocrine manner by Paneth cells. 1 Wnt signals inactivate the kinase GSK3β, resulting in stabilization of β-catenin and transcription of β-catenin/TCF4 target genes. 6 Wnt/β-catenin signals in the crypt are required for ISC maintenance.…”

Section: Introductionmentioning

confidence: 99%

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Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF V637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.

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Section: Above)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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“…These findings suggest that, as in the differentiation process, the transcriptional response of intestinal cells to the microbiota is regulated mainly by the differential binding of SDTFs, independently of changes in chromatin accessibility. One hypothesis is that in cells with such a short lifespan of 3-5 days [50], it may be more effective to have inducible TFs operating in an already accessible, and therefore permissive, chromatin landscape to respond to an insult. Comprehensive experimentation in other cell types that have also a relatively medium to high turnover and are equally capable of mounting an innate response such as lung epithelial cells [51] or skin keratinocytes [52] may allow us to derive a more general picture.…”

Section: H3k27ac H3k4me1mentioning

confidence: 99%

Gene regulatory mechanisms underlying the intestinal innate immune response

Meireles-Filho

Deplancke

2017

Current Opinion in Genetics & Development

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In the mammalian gastrointestinal tract, distinct types of cells, including epithelial cells and macrophages, collaborate to eliminate ingested pathogens while striving to preserve the commensal microbiota. The underlying innate immune response is driven by significant gene expression changes in each cell, and recent work has provided novel insights into the gene regulatory mechanisms that mediate such transcriptional changes. These mechanisms differ from those underlying the canonical cellular differentiation model in which a sequential deposition of DNA methylation and histone modification marks progressively restricts the chromatin landscape. Instead, inflammatory macrophages and intestinal epithelial cells appear to largely rely on transcription factors that explore an accessible chromatin landscape to generate dynamic stimulus-specific and spatial-specific physiological responses.

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“…On the other hand, regenerative events in more complex organisms, such as regeneration of a vertebrate limb, heart, or retina, depends on cells with limited lineage differentiation potential, which often arise from dormant or dedifferentiated cells (reviewed by Jopling et al, 2011). Humans continuously repair their intestinal epithelium through use of small reservoirs of intestinal stem cells that continuously proliferate and differentiate into a handful of epithelial cell types (reviewed by Barker, 2014). These cells, however, would be expected to fail at restoring damaged tissue outside the intestine under normal conditions, due to their limited potency.…”

Section: Labib Rouhana and Junichi Tasakimentioning

confidence: 99%

A primer on regeneration

Rouhana

Tasaki

2015

Preprint

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Centuries of observation have uncovered a diverse range of organisms capable of overcoming loss of tissue. The act of restoring lost anatomy and function is known as regeneration, and it is broadly represented in both plant and animal kingdoms. Cumulative studies have identified a series of events that take place during regeneration of complex animal structures. First, the organism recognizes damage and undergoes wound healing. Then, programmed cell death in the vicinity of the damaged tissue precedes proliferation and migration of cells that foster the development of replacement tissue. Finally, rearrangement of pre-existing tissue and integration with newly differentiated cells take place to restore the function and proportionality displayed previous to damage . Although the ability to regenerate is believed to be ancestrally common and lost throughout evolution, there is significant heterogeneity of some basic mechanisms displayed during regeneration in different animal species. Perhaps one of the most noticeable differences is the cellular source contributing to formation of the new tissue during regeneration. Organisms such as planarians and Hydra rely on active reservoirs of somatic pluripotent stem cells abundantly distributed throughout their bodies and maintained throughout their life. On the other hand, vertebrates rely mostly on progenitor cell activation and dedifferentiation, to regenerate cells with limited potential to regenerate specific structures. However, not all regenerative events rely on cellular replacement. Leading edge research has begun to uncover mechanisms involved in autonomous repair and functional regeneration of single cells – be it neurons or ciliated protozoa. The fact that organisms can achieve regeneration through diverse cellular sources is remarkable, but just as remarkable is the possibility that conserved molecular pathways could be activated to achieve regeneration in different species. Analysis of these pathways will contribute to understanding human development and potential avenues for regenerative medicine.

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Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration

Cited by 1,042 publications

References 121 publications

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Gene regulatory mechanisms underlying the intestinal innate immune response

A primer on regeneration

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