Rapid Crypt Cell Remodeling Regenerates the Intestinal Stem Cell Niche after Notch Inhibition

Bohin, Natacha; Keeley, Theresa M.; Carulli, Alexis J.; Walker, Emily M.; Carlson, Elizabeth A.; Gao, Jie; Aifantis, Iannis; Siebel, Christian W.; Rajala, Michael W.; Myers, Martin G.; Jones, Jennifer; Brindley, Constance D.; Dempsey, Peter J.; Samuelson, Linda C.

doi:10.1016/j.stemcr.2020.05.010

Cited by 19 publications

(29 citation statements)

References 53 publications

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“…3). A recent study showed that acute Notch inhibition leads to rapid apoptosis of PCs, while Notch activation counteracts the death of PCs caused by caspase-8 (casp8) absence; these finding suggests that Notch signalling are required for PC maintenance [43,113].…”

Section: Growth Factor-mediated Signalling Pathways Regulate the Devementioning

confidence: 99%

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Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Mei

2020

Stem Cell Res Ther

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Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies reported on how PCs shape the intestinal microbiota or the response to the immune system. Recent studies have determined that PCs play an important role in the regulation of the homeostasis of intestinal epithelial cells. PCs can regulate the function and homeostasis of intestinal stem cells through several mechanisms. On the one hand, under pathological conditions, PCs can be dedifferentiated into stem cells to promote the repair of intestinal tissues. On the other hand, PCs can regulate stem cell proliferation by secreting a variety of hormones (such as wnt3a) or metabolic intermediates. In addition, we summarise key signalling pathways that affect PC differentiation and mutual effect with intestinal stem cells. In this review, we introduce the diverse functions of PCs in the intestine.

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Section: Growth Factor-mediated Signalling Pathways Regulate the Devementioning

confidence: 99%

“…A subset of neuroD1-derived EECs can reserve stem cell properties in response to radiation-induced injury or under homeostatic conditions [42]. Upon intestinal injury, Dll1-and Dll4-expressing cells generate absorptive and secretory cells [43].…”

Section: Contribution Of Paneth Cells To Intestinal Epithelium Renewalmentioning

confidence: 99%

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Mei

2020

Stem Cell Res Ther

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“… 6 Secretory precursors and differentiated Paneth cells have a modest but variable (0–50 lineage trace events per 5 cm) 17 contribution to epithelial regeneration that has been identified in multiple studies. 15 , 17 , 19 , 23 This reversion phenomenon appears dependent on Notch activation after DXR and IR. 17 , 18 , 19 …”

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confidence: 95%

“… 8 , 9 , 10 Recent studies demonstrate that Bmi1 marks cells of the enteroendocrine lineage. 11 Others have demonstrated the inherent plasticity of the intestinal epithelium, with varying degrees of regeneration originating from Dll1 + or Atoh1 + secretory progenitors, 12 , 13 , 14 , 15 differentiated Alpi1 + enterocyte precursors, 16 and differentiated Defa4 + , Lyz1 + , or Bhlha15 + Paneth cells. 17 , 18 , 19 …”

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confidence: 99%

Epithelial Regeneration After Doxorubicin Arises Primarily From Early Progeny of Active Intestinal Stem Cells

Sheahan

Freeman

Keeley

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims aISCs (aISCs) are sensitive to acute insults including chemotherapy and irradiation. Regeneration after aISC depletion has primarily been explored in irradiation (IR). However, the cellular origin of epithelial regeneration after doxorubicin (DXR), a common chemotherapeutic, is poorly understood. Methods We monitored DXR’s effect on aISCs by enumerating Lgr5-eGFP + and Olfm4 + crypts, cleaved caspase-3 (CASP3 + ) immunofluorescence, and time-lapse organoid imaging. Lineage tracing from previously identified regenerative cell populations ( Bmi1 + , Hopx + , Dll1 + , and Defa6 + ) was performed with DXR damage. Lineage tracing from aISCs was compared with lineage tracing from early progeny cells (transit-amplifying cells arising from aISCs 1 day predamage) in the context of DXR and IR. We compared stem cell and DNA damage response (DDR) transcripts in isolated aISCs and early progeny cells 6 and 24 hours after DXR. Results Epithelial regeneration after DXR primarily arose from early progeny cells generated by aISCs. Early progeny cells upregulated stem cell gene expression and lacked apoptosis induction (6 hours DXR: 2.5% of CASP3 + cells, p<0.0001). aISCs downregulated stem cell gene expression and underwent rapid apoptosis (6 hours DXR: 63.4% of CASP3 + cells). There was minimal regenerative contribution from Bmi1 + , Hopx + , Dll1 + , and Defa6 + -expressing populations. In homeostasis, 48.4% of early progeny cells were BrdU + , and expressed low levels of DDR transcripts. Conclusions We show that DXR effectively depleted aISCs in the small intestine and subsequent epithelial regeneration depended on nonquiescent early progeny cells of aISCs. The chemoresistant phenotype of the early progeny cells may rely on a dampened DDR in contrast to aISCs’ robust DDR, which facilitates expeditious apoptosis.

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“…Somewhat surprisingly, this triggers rapid apoptotic demise of Notch ligand-bearing Paneth cells, leaving Lgr5 + ISCs intact, albeit with diminished lineage-tracing capacity. Nevertheless, in this setting, both Lgr5 + ISCs (that activate expression of Dll1 ) and Dll1 + multipotent progenitors can mobilize to replenish the depleted Paneth cell pool and restore Notch homeostasis [ 141 ]. While these results contrast with the loss of Lgr5 + ISCs and the expansion of Paneth-like cells observed during prolonged Notch inhibition [ 84 ], they attest to the potential tolerability of transient Notch perturbation in the clinic and underscore that different modes of injury elicit distinct cellular and molecular responses.…”

Section: Niche Remodelling Post Injurymentioning

confidence: 99%

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

Sphyris

Hodder

Sansom

2021

Cancers

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The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints (“ISC emancipation”) and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.

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Rapid Crypt Cell Remodeling Regenerates the Intestinal Stem Cell Niche after Notch Inhibition

Cited by 19 publications

References 53 publications

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Epithelial Regeneration After Doxorubicin Arises Primarily From Early Progeny of Active Intestinal Stem Cells

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

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