URI is required to maintain intestinal architecture during ionizing radiation

Perez, Almudena Chaves; Yilmaz, M. Deniz; Perna, Cristian; Rosa, Sergio de la; Djouder, Nabil

doi:10.1126/science.aaq1165

Cited by 50 publications

(44 citation statements)

References 37 publications

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“…Although our data indicate that it is the rapidly-cycling Msi1 + ISCs that survive irradiation exposure and repopulate damaged epithelium, we cannot formally rule out the previously proposed model that quiescent ISCs and/or precursors also contribute to epithelial regeneration (Ayyaz, Kumar et al, 2019, Chaves-Perez, Yilmaz et al, 2019, Yan et al, 2017. It is noteworthy that, while many secretory progenitor cells, marked by Dll1-CreERT (van Es et al, 2012), Prox1-CreERT (Yan et al, 2017), or H2B-label (Buczacki et al, 2013), have regenerative capacity, the contribution of these cells to epithelial regeneration are limited (Bankaitis, Ha et al, 2018).…”

Section: Discussionmentioning

confidence: 59%

Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells

Sheng

Lin

et al. 2019

Preprint

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The +4 cells in intestinal crypts are DNA damage-resistant and contribute to regeneration. However, their exact identity and the mechanism underlying +4 cell-mediated regeneration remain unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1 + ) are enriched at the +4 position in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1 + cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1 + cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5 high radio-sensitive crypt base columnar stem cells (CBCs); they enable fast repopulation of the intestinal epithelium independent of CBCs that are largely depleted after irradiation. Furthermore, relative to CBCs, Msi1 + cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1 + cells are rapidly cycling ISCs that maintain and regenerate the intestinal epithelium.

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Section: Discussionmentioning

confidence: 59%

Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells

Sheng

Lin

et al. 2019

Preprint

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“…Homologous recombination (HR) and non-homologous end joining (NHEJ) and are the two main modes to repair DSBs in mammalian cells, in which ATR and ATM are con rmed to be the key components of DNA damage response (DDR) pathway [22,23]. As DDR is critical for the maintenance and modulation of genome integrity in intestinal cells after radiation exposure [33,34], we speculated that the radio-protective effects of HKST might be involved in DDR. As our results show that, after radiation exposure, levels of P-ATM, P-ATR, P-CHK1 and p21 were signi cantly increased in cells pretreated with HKST (Fig.…”

Section: Discussionmentioning

confidence: 99%

Heat Killed Salmonella typhimurium protects intestine against radiation injury through Wnt signaling pathway

Chen

Cao

et al. 2020

Preprint

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Purpose: Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) appears to be a limited factor in radiotherapy and a great threat for soldiers on nuclear-related military missions. However, there are currently no approved medical strategies to effectively prevent or mitigate the damage on intestine induced by IR. The present study aimed to elucidate the protective activity of Heat Killed Salmonella typhimurium (HKST) on intestine against ionizing radiation exposure. Materials and Methods: Mouse intestinal crypts and intestinal organoids were isolated from C57BL/6J mice. Mice and HIEC cells were exposed to 60Co γ‐radiation. The dosage was set as following: whole body radiation of 8 Gy; mouse intestinal organoids were irradiated with 0 Gy, 4 Gy, and 6 Gy of γ-rays at dose rate of 1 Gy/min. Cells or mice were pretreated with Heat Killed Salmonella typhimurium (HKST) (107 cells/mice) at 12 hours prior to irradiation.Results: By culturing mouse intestinal organoids and employing whole body irradiation of mice, we found that the radiation-induced damage on intestine was dramatically mitigated by pretreating with HSKT in vitro and in vivo, in which the structure of intestinal organoids and small intestine of the HKST-treated group was more integrated than of the radiation damage group, and HKST pretreatment remarkably promoted the proliferation of intestinal cells post IR exposure (Figure 1 and 2). Further study showed that the radio-protective effects of HKST was involved in DNA damage response (DDR) signaling. Moreover, the stimulation of DDR signaling by HKST upon radiation damage was mediated by Wnt signaling, in which the inhibition of Wnt signaling diminished the radio-protective effects of HKST. Conclusion: Our study demonstrated that Heat Killed Salmonella typhimurium (HKST) could significantly alleviate the damage on intestine induced by IR, and the radio-protective effect of HKST was depended on DDR mediated by Wnt signaling pathway. These findings demonstrated that HKST is a potential bacterium using for the prevention of IR-induced GI toxicity in clinical practice.

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“…URI has strong oncogenic activity because it can regulate the functions of many proteins including transcription factors (ERα and AhR) [86]. For example, in a mouse model, excessive expression of URI in hepatocytes can lead to hepatocellular carcinoma (HCC) [85]; decreasing the expression of URI in the intestine will activate the c-Myc expression induced by β-catenin, leading to mouse cell proliferation, DNA damage, and susceptibility to fatal gastrointestinal syndrome (GIS) caused by ionizing radiation (IR) [88]. In addition, URI can induce resistance of cervical cancer [89], colorectal cancer [90], and gastric cancer cells [91], and promote cell survival.…”

Section: Prefoldin Subunits Are Involved In the Assemble Of Prefoldinmentioning

confidence: 99%

The functions and mechanisms of prefoldin complex and prefoldin-subunits

et al. 2020

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The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins. Prefoldin plays a crucial role in the pathogenesis of common neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and Huntington's disease). The important role of prefoldin in emerging fields (such as nanoparticles, biomaterials) and tumors has attracted widespread attention. Also, each of the prefoldin subunits has different and independent functions from the prefoldin complex. It has abnormal expression in different tumors and plays an important role in tumorigenesis and development, especially c-Myc binding protein MM-1. MM-1 can inhibit the activity of c-Myc through various mechanisms to regulate tumor growth. Therefore, an in-depth analysis of the complex functions of prefoldin and their subunits is helpful to understand the mechanisms of protein misfolding and the pathogenesis of diseases caused by misfolded aggregation.

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URI is required to maintain intestinal architecture during ionizing radiation

Cited by 50 publications

References 37 publications

Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells

Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells

Heat Killed Salmonella typhimurium protects intestine against radiation injury through Wnt signaling pathway

The functions and mechanisms of prefoldin complex and prefoldin-subunits

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URI is required to maintain intestinal architecture during ionizing radiation

Cited by 50 publications

References 37 publications

Rapidly cycling stem cells regenerate the intestine independent ofLgr5highcells

Rapidly cycling stem cells regenerate the intestine independent ofLgr5highcells

Heat Killed Salmonella typhimurium protects intestine against radiation injury through Wnt signaling pathway

The functions and mechanisms of prefoldin complex and prefoldin-subunits

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Product

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Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells

Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells