Cycling Stem Cells Are Radioresistant and Regenerate the Intestine

Sheng, Xiaole; Lin, Ziguang; Lv, Cong; Shao, Chunlei; Bi, Xueyun; Deng, Min; Xu, Jiuzhi; Guerrero‐Juarez, Christian F.; Li, Mengzhen; Wu, Xi; Zhao, Ran; Xu, Yang; Li, Guilin; Liu, Xiaowei; Wang, Qingyu; Nie, Qing; Cui, Wei; Gao, Shan; Zhang, Hongquan; Liu, Zhihua; Cong, Yingzi; Plikus, Maksim V.; Lengner, Christopher J.; Andersen, Bogi; Ren, Fazheng; Yu, Zhengquan

doi:10.1016/j.celrep.2020.107952

Cited by 48 publications

(43 citation statements)

References 53 publications

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“…Situated just above the last Paneth cell in the crypt are the +4 position cells, which have a unique transcriptional profile including expression of Hopx (Takeda et al, 2011), Tert (Breault et al, 2008;Montgomery et al, 2011), Bmi1 (Sangiorgi and Capecchi, 2008), and Lrig1 (Powell et al, 2012) (Figure 2). These cells have previously been deemed the RSC population, which reconstitutes Lgr5 + CBCs during a state of injury (Breault et al, 2008;Sangiorgi and Capecchi, 2008;Montgomery et al, 2011;Powell et al, 2012), and have been previously shown to be radiation resistant (Tao et al, 2017;Montenegro-Miranda et al, 2020;Sheng et al, 2020), suggesting that these cells can survive acute injury in the crypt and fill in for their damaged counterparts. However, recent literature has underscored the complexity of characterizing these cells and called into question their "stemness."…”

Section: The Role Of +4 Position Cells and Secretory Precursors In Rementioning

confidence: 99%

“…Msi1 has previously been identified as a marker of ISCs (CBCs, and +4 position cells) (Kayahara et al, 2003;Li et al, 2015). Sheng et al (2020) set out to understand if Msi1 can rapidly cycle to restore a damaged intestinal epithelium. This was investigated by generating an Msi1CreERT2 allele for lineage tracing analysis and this led to the discovery that Msi1 + cells are indeed positioned in the +4 position in the intestinal crypt and are resistant to DNA damage via y-irradiation.…”

Section: Msi1 and Tigar: Boosting The Potential Of Darscsmentioning

confidence: 99%

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Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Rees

Tandun

Yau

et al. 2020

Front. Cell Dev. Biol.

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The intestinal epithelium is replenished every 3–4 days through an orderly process that maintains important secretory and absorptive functions while preserving a continuous mucosal barrier. Intestinal epithelial cells (IECs) derive from a stable population of intestinal stem cells (ISCs) that reside in the basal crypts. When intestinal injury reaches the crypts and damages IECs, a mechanism to replace them is needed. Recent research has highlighted the existence of distinct populations of acute and chronic damage-associated ISCs and their roles in maintaining homeostasis in several intestinal perturbation models. What remains unknown is how the damage-associated regenerative ISC population functions in the setting of chronic inflammation, as opposed to acute injury. What long-term consequences result from persistent inflammation and other cellular insults to the ISC niche? What particular “regenerative” cell types provide the most efficacious restorative properties? Which differentiated IECs maintain the ability to de-differentiate and restore the ISC niche? This review will cover the latest research on damage-associated regenerative ISCs and epigenetic factors that determine ISC fate, as well as provide opinions on future studies that need to be undertaken to understand the repercussions of the emergence of these cells, their contribution to relapses in inflammatory bowel disease, and their potential use in therapeutics for chronic intestinal diseases.

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Section: The Role Of +4 Position Cells and Secretory Precursors In Rementioning

confidence: 99%

Section: Msi1 and Tigar: Boosting The Potential Of Darscsmentioning

confidence: 99%

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Rees

Tandun

Yau

et al. 2020

Front. Cell Dev. Biol.

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show abstract

“…To investigate this possibility, we repeated the experiment and assessed tumor burden and signs of intestinal regeneration at day three after irradiation (Figure 4D) . Although this was an early timepoint for assessment of tumor radiation response, attempts at intestinal regeneration are frequently assessed around this timepoint (Metcalfe et al, 2014; Olcina and Giaccia, 2016; Sheng et al, 2020; Wei et al, 2016). We indeed observed that three days post irradiation the majority of mice showed signs of early regeneration (Supplementary Figure 4) .…”

Section: Resultsmentioning

confidence: 99%

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

Olcina

Melemenidis

Nambiar

et al. 2020

Preprint

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Engaging innate immune pathways is emerging as a productive way of achieving durable anti-tumor responses. However, systemic administration of these therapies can result in toxicity, deemed to be particularly problematic when combined with current standard-of-care cytotoxic treatments such as radiotherapy. Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies, however, few pre-clinical studies investigate both tumor and normal tissue responses in detail. Here we show that targeting innate immune receptor C5aR1 improves tumor radiation response while reducing radiation-induced normal tissue toxicity, thereby increasing the therapeutic window. The potent and orally active C5aR1 inhibitor, PMX205, increases IL-10 secretion, which attenuates RelA phosphorylation and enhances apoptosis in tumor cells. Importantly, targeting C5aR1 improves tumor radiation response even in the presence of reduced CD8+ T-cell infiltration, suggesting that this is a good target even in tumors displaying features of T-cell deficiency or exclusion. Furthermore, we find that C5aR1 depletion results in decreased small intestinal histologic damage, crypt cell apoptosis and increased survival of mice following irradiation. Using a preclinical murine model allowing the simultaneous assessment of tumor and normal tissue radiation responses, we show that PMX205 treatment reduces histological and functional markers of small-bowel toxicity while affording a positive tumor response. Our data, therefore, suggest that targeting C5aR1 could be a promising approach for increasing the therapeutic window of radiotherapy.

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“…We next sought to characterize changes in cellular composition after ALI to assess differentiation and emergence of damageassociated regenerative stem cells (DARSCs), as previously noted in models of acute damage (Breault et al, 2008;Montenegro-Miranda et al, 2020;Montgomery et al, 2011;Murata et al, 2020;Powell et al, 2012;Sangiorgi and Capecchi, 2008;Sheng et al, 2020;Takeda et al, 2011;Tao et al, 2017), including submergence damage (Wang et al, 2019). Compared with day 10 submerged growth, ALI culture caused differentiation of colonoid monolayers, with increased expression of MUC2, SLC26a3 (DRA), and CHGA (Figure 2A).…”

Section: Repeated Submergence Injury Induces Differentiation Of Colon...mentioning

confidence: 95%

An in vitro chronic damage model impairs inflammatory and regenerative responses in human colonoid monolayers

et al. 2022

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Cycling Stem Cells Are Radioresistant and Regenerate the Intestine

Abstract: Highlights d Cycling Msi1 + ISCs in the intestinal crypt are DNA damage resistant d Msi1 + ISCs enable fast intestinal repair ahead of Lgr5 high CBCs d Paneth cells preferentially arise from Msi1 + ISCs during homeostasis and repair

Cited by 48 publications

References 53 publications

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

An in vitro chronic damage model impairs inflammatory and regenerative responses in human colonoid monolayers

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