colonic stem cells
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2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Shuo Zhang ◽  
Wei-Wei Ji ◽  
Wei Wei ◽  
Li-Xing Zhan ◽  
Xuan Huang

Abstract Background Colorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNA Meg3, which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by which Meg3 contributes to the malignant proliferation of colonic stem cells remains unclear. Methods We analyzed the expression levels of Meg3, miR-708, and SOCS3 in samples from Apc loss-of-function (Apcmin) mice and patients with CRC, particularly in colonic crypt cells. Apcmin mice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of the Meg3/miR-708/SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines. Findings The Meg3/miR-708/SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showed Meg3 levels negatively correlate with miR-708 levels both in clinical samples and in the Apcmin mouse model, which indicated that Meg3 acts as a competitive endogenous RNA (ceRNA) of miR-708. Then, miR-708 served as an oncogene, inducing neoplasia in both Apcmin mice and cultured colonic organoids. Put together, miR-708 appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling. Interpretation These data revealed that Meg3 sponges miR-708 to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. The Meg3/miR-708/SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.


2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Guoli Zhu ◽  
Rongwen Xi

AbstractIncreasing evidence suggest functional roles of subepithelial mesenchymal niche cells in maintaining intestinal stem cells and in modulating the pathogenesis of various intestinal diseases in mammals. A recent study reported the discovery of a new population of stromal cells in mice termed MAP3K2-Regulated Intestinal Stromal Cells (MRISCs); these cells reside at the base of colonic crypt and function to protect colonic stem cells during colonic inflammation by expressing the Wnt agonist R-spondin1 (Rspo1).


2020 ◽  
Vol 21 (8) ◽  
pp. 2804 ◽  
Author(s):  
Vignesh Viswanathan ◽  
Lynn Opdenaker ◽  
Shirin Modarai ◽  
Jeremy Z. Fields ◽  
Gregory Gonye ◽  
...  

MicroRNAs (miRNAs) have a critical role in regulating stem cells (SCs) during development, and because aberrant expression of miRNAs occurs in various cancers, our goal was to determine if dysregulation of miRNAs is involved in the SC origin of colorectal cancer (CRC). We previously reported that aldehyde dehydrogenase (ALDH) is a marker for normal and malignant human colonic SCs and tracks SC overpopulation during colon tumorigenesis. MicroRNA expression was studied in ALDH-positive SCs from normal and malignant human colon tissues by Nanostring miRNA profiling. Our findings show that: (1) A unique miRNA signature distinguishes ALDH-positive CRC cells from ALDH-positive normal colonic epithelial cells, (2) Expression of four miRNAs (miRNA200c, miRNA92a, miRNA20a, miRNA93) are significantly altered in CRC SCs compared to normal colonic SCs, (3) miRNA92a expression is also upregulated in ALDH-positive HT29 CRC SCs as compared to ALDH-negative SCs, (4) miRNA92a targets the 3′UTR of LRIG1 SC gene, and (5) miRNA92a modulates proliferation of HT29 CRC cells. Thus, our findings indicate that overexpression of miRNA92a contributes to the SC origin of CRC. Strategies designed to modulate miRNA expression, such as miRNA92a, may provide ways to target malignant SCs and to develop more effective therapies against CRC.


2020 ◽  
Vol 117 (14) ◽  
pp. 8064-8073 ◽  
Author(s):  
Steven J. Mileto ◽  
Thierry Jardé ◽  
Kevin O. Childress ◽  
Jaime L. Jensen ◽  
Ashleigh P. Rogers ◽  
...  

Gastrointestinal infections often induce epithelial damage that must be repaired for optimal gut function. While intestinal stem cells are critical for this regeneration process [R. C. van der Wath, B. S. Gardiner, A. W. Burgess, D. W. Smith,PLoS One8, e73204 (2013); S. Kozaret al.,Cell Stem Cell13, 626–633 (2013)], how they are impacted by enteric infections remains poorly defined. Here, we investigate infection-mediated damage to the colonic stem cell compartment and how this affects epithelial repair and recovery from infection. Using the pathogenClostridioides difficile,we show that infection disrupts murine intestinal cellular organization and integrity deep into the epithelium, to expose the otherwise protected stem cell compartment, in a TcdB-mediated process. Exposure and susceptibility of colonic stem cells to intoxication compromises their function during infection, which diminishes their ability to repair the injured epithelium, shown by altered stem cell signaling and a reduction in the growth of colonic organoids from stem cells isolated from infected mice. We also show, using both mouse and human colonic organoids, that TcdB from epidemic ribotype 027 strains does not require Frizzled 1/2/7 binding to elicit this dysfunctional stem cell state. This stem cell dysfunction induces a significant delay in recovery and repair of the intestinal epithelium of up to 2 wk post the infection peak. Our results uncover a mechanism by which an enteric pathogen subverts repair processes by targeting stem cells during infection and preventing epithelial regeneration, which prolongs epithelial barrier impairment and creates an environment in which disease recurrence is likely.


Cell ◽  
2019 ◽  
Vol 179 (5) ◽  
pp. 1144-1159.e15 ◽  
Author(s):  
Yi Wang ◽  
I-Ling Chiang ◽  
Takahiro E. Ohara ◽  
Satoru Fujii ◽  
Jiye Cheng ◽  
...  

2019 ◽  
Vol 3 (19) ◽  
pp. 2866-2869 ◽  
Author(s):  
Jonathan L. Golob ◽  
Martha M. DeMeules ◽  
Tillie Loeffelholz ◽  
Z. Z. Quinn ◽  
Michael K. Dame ◽  
...  

Key Points The presence of butyrogenic bacteria after the onset of acute GVHD associates with subsequent steroid-refractory GVHD or chronic GVHD. Butyrate inhibits human colonic stem cells from forming an intact epithelial monolayer.


2018 ◽  
Vol 86 (6) ◽  
pp. 1577-1587
Author(s):  
SAED ROSIQ, M.D.; OLFAT HAMMAM, M.D. ◽  
AHMED ABD EL-ALIM, M.D.; SAED EL-SHORBAGY, M.D. ◽  
MOSBAH AMER, M.Sc.

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