Intestinal stem cells promote crypt fission during postnatal growth of the small intestine

Dudhwala, Zenab M.; Hammond, Paul; Howarth, Gordon S.; Cummins, Adrian G.

doi:10.1136/bmjgast-2020-000388

Cited by 16 publications

(9 citation statements)

References 33 publications

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“…They reside exclusively at the bottom of crypts wedged between Paneth cells. CBCs divide every 21–24 h in mice and produce two equipotent daughter cells ( Dudhwala et al, 2020 ). Each crypt contains around 15 intestinal stem cells (mouse) although stem cell numbers vary with age.…”

Section: Simple Yet Diverse – the Intestinal Epitheliummentioning

confidence: 99%

“…Each crypt contains around 15 intestinal stem cells (mouse) although stem cell numbers vary with age. In humans, stem cell numbers are high from birth throughout teenage years, but drop threefold in adults ( Dudhwala et al, 2020 ). In rodents and humans CBCs are identifiable by their expression of LGR5, a receptor for R-spondins (RSPO) ( Barker et al, 2007 ).…”

Section: Simple Yet Diverse – the Intestinal Epitheliummentioning

confidence: 99%

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The Intestinal Epithelium – Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip

Bonis

Rossell

Gehart

2021

Front. Cell Dev. Biol.

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The single-layered, simple epithelium of the gastro-intestinal tract controls nutrient uptake, coordinates our metabolism and shields us from pathogens. Despite its seemingly simple architecture, the intestinal lining consists of highly distinct cell populations that are continuously renewed by the same stem cell population. The need to maintain balanced diversity of cell types in an unceasingly regenerating tissue demands intricate mechanisms of spatial or temporal cell fate control. Recent advances in single-cell sequencing, spatio-temporal profiling and organoid technology have shed new light on the intricate micro-structure of the intestinal epithelium and on the mechanisms that maintain it. This led to the discovery of unexpected plasticity, zonation along the crypt-villus axis and new mechanism of self-organization. However, not only the epithelium, but also the underlying mesenchyme is distinctly structured. Several new studies have explored the intestinal stroma with single cell resolution and unveiled important interactions with the epithelium that are crucial for intestinal function and regeneration. In this review, we will discuss these recent findings and highlight the technologies that lead to their discovery. We will examine strengths and limitations of each approach and consider the wider impact of these results on our understanding of the intestine in health and disease.

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Section: Simple Yet Diverse – the Intestinal Epitheliummentioning

confidence: 99%

Section: Simple Yet Diverse – the Intestinal Epitheliummentioning

confidence: 99%

The Intestinal Epithelium – Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip

Bonis

Rossell

Gehart

2021

Front. Cell Dev. Biol.

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“…Overexpression of the Wnt inhibitor Dkk1 leads to a loss of crypts and reduced epithelial proliferation[ 37 ]. Furthermore, inhibition of Dkk leads to a reduced rate of fission of crypts in postnatal growth[ 38 ]. A negative autoregulatory feedback loop of Wnt signaling prevents a hyperactivation of Wnt signaling[ 28 , 39 ].…”

Section: The Necessity Of Wnt Signaling In Intestinal Mucosal Physiologymentioning

confidence: 99%

Intestinal Wnt in the transition from physiology to oncology

Swoboda¹,

Mittelsdorf²,

Chen³

et al. 2022

WJCO

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Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.

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“…In neonatal life intestinal and colonic elongation occurs through crypt fission ( Figure 1 ). In crypt fission LGR5+ epithelial stem cells proliferate increasing the size of the crypt ( 9 ). The crypt then divides forming two crypts ( 10 ).…”

Section: Tlr4 Signaling Regulates Epithelial Proliferation In Intestimentioning

confidence: 99%

Nonmicrobial Activation of TLRs Controls Intestinal Growth, Wound Repair, and Radioprotection

Stenson

Ciorba

2021

Front. Immunol.

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TLRs, key components of the innate immune system, recognize microbial molecules. However, TLRs also recognize some nonmicrobial molecules. In particular, TLR2 and TLR4 recognize hyaluronic acid, a glycosaminoglycan in the extracellular matrix. In neonatal mice endogenous hyaluronic acid binding to TLR4 drives normal intestinal growth. Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE2 production, which transactivates EGFR in LGR5+ crypt epithelial stem cells leading to increased proliferation. The expanded population of LGR5+ stem cells leads to crypt fission and lengthening of the intestine and colon. Blocking this pathway at any point (TLR4 activation, PGE2 production, EGFR transactivation) results in diminished intestinal and colonic growth. A similar pathway leads to epithelial proliferation in wound repair. The repair phase of dextran sodium sulfate colitis is marked by increased epithelial proliferation. In this model, TLR2 and TLR4 in pericryptal macrophages are activated by microbial products or by host hyaluronic acid, resulting in production of CXCL12, a chemokine. CXCL12 induces the migration of cyclooxygenase2-expressing mesenchymal stem cells from the lamina propria of the upper colonic crypts to a site adjacent to LGR5+ epithelial stem cells. PGE2 released by these mesenchymal stem cells transactivates EGFR in LGR5+ epithelial stem cells leading to increased proliferation. Several TLR2 and TLR4 agonists, including hyaluronic acid, are radioprotective in the intestine through the inhibition of radiation-induced apoptosis in LGR5+ epithelial stem cells. Administration of exogenous TLR2 or TLR4 agonists activates TLR2/TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2-expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells. PGE2 produced by these mesenchymal stem cells, blocks radiation-induced apoptosis in LGR5+ epithelial stem cells by an EGFR mediated pathway.

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Intestinal stem cells promote crypt fission during postnatal growth of the small intestine

Cited by 16 publications

References 33 publications

The Intestinal Epithelium – Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip

The Intestinal Epithelium – Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip

Intestinal Wnt in the transition from physiology to oncology

Nonmicrobial Activation of TLRs Controls Intestinal Growth, Wound Repair, and Radioprotection

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