A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis

Tan, Si Hui; Phuah, Phyllis; Tan, Liang Juin; Yada, Swathi; Goh, Jonathan; Tomaz, Lucian B.; Chua, Magdalene; Wong, Esther; Lee, Bernett; Barker, Nick

doi:10.1016/j.celrep.2020.108633

Cited by 41 publications

(45 citation statements)

References 24 publications

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“…In support of this notion, when Rspo3 is deleted in both LECs and RGFs using Grem1-CreERT2; Prox1-CreERT2; Rspo3 f/f mice, we now observed a dramatic decrease in the numbers of Olfm4+ or Lgr5+ ISCs that is accompanied by shortened crypt-villus units and crypts in the small intestine and the colon, respectively (Figures 5C-J). These phenotypical changes emulate the morphological changes observed in a new model of diphtheria toxin mediated ablation of Lgr5+ ISCs (Tan et al, 2021).…”

Section: Lecs and Rgfs Support Iscs And Post-injury Regeneration In Vivosupporting

confidence: 72%

Lymphatics constitute a novel component of the intestinal stem cell niche

Goto

Imada

Yılmaz

2022

Preprint

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Intestinal stem cells (ISCs) depend on niche factors for their proper function. However, the source of these ISC niche factors and how they support ISCs remain controversial due to their redundant expression patterns. Here, we report that the maintenance of ISCs depends on both lymphatic endothelial cells (LECs) and Rspo3+Grem1+ fibroblasts (RGFs). We found that LECs are surrounded by RGFs and located in close proximity to Lgr5+ ISCs. RSPO3 production is restricted to LECs and RGFs and they can partially compensate for each other; however, RSPO3 loss in both of LECs and RGFs drastically compromises ISC numbers, villi length, and repair after irradiation-induced injury. Mechanistically, irradiation-induced damage expands LEC and RGF numbers and enhances the generation of RSPO3 in RGFs through IL-1 receptor activation. We propose that LECs represent a novel component of the ISC niche, which together with RGFs, provide essential RSPO3 to sustain ISCs in homeostasis and regeneration.

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Section: Lecs and Rgfs Support Iscs And Post-injury Regeneration In Vivosupporting

confidence: 72%

Lymphatics constitute a novel component of the intestinal stem cell niche

Goto

Imada

Yılmaz

2022

Preprint

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“…Interestingly, in all cases LGR5 + cells re-appeared within 2–3 days after complete removal. However, when their resurgence was blocked due to continuous DT-mediated ablation, the regeneration process failed ( Metcalfe et al, 2014 ; Tan et al, 2021 ). This implies that the LGR5 + cell pool is essential for intestinal regeneration, but can be replenished by an alternative cell source.…”

Section: Cellular and Tissue Plasticity In 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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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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“…Indeed, we found a significant decrease in the percentage of CD44 + cells that are Lgr5 + with EIPA compared with controls. Lgr5 + ISCs will differentiate by default in the absence of Wnt-signaling (19,20), and loss of Lgr5 + ISCs causes crypt loss in organoids (21) and in vivo (22)(23)(24)(25). Therefore, these data suggest that inhibiting NHE1 activity attenuates crypt budding and growth by interfering with the maintenance of Lgr5 + ISCs.…”

Section: Nhe1 Activity Is Necessary For Crypt Growthmentioning

confidence: 84%

Intracellular pH dynamics regulates intestinal stem cell lineage specification

Liu

Reyes

Castillo-Azofeifa

et al. 2021

Preprint

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SummaryEmerging evidence is revealing critical roles of intracellular pH (pHi) in development (1–4), but it remains unclear whether pHi regulates stem cell fate specification. We find that pHi dynamics is a key regulator of cell fate in the mouse intestinal stem cell lineage. We identify a pHi gradient along the intestinal crypt axis and find that dissipating this gradient inhibits crypt budding due to loss Paneth cell differentiation. Mechanistically, decreasing pHi biases intestinal stem cell fate toward the absorptive and away from the secretory lineage, by regulating the activity of the lineage transcription factor Atoh1. Our findings reveal a previously unrecognized role for pHi dynamics in the specification of cell fate within an adult stem cell lineage.

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A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis

Cited by 41 publications

References 24 publications

Lymphatics constitute a novel component of the intestinal stem cell niche

Lymphatics constitute a novel component of the intestinal stem cell niche

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

Intracellular pH dynamics regulates intestinal stem cell lineage specification

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