Introduction to themed series on intestinal stem cells and the NIDDK Intestinal Stem Cell Consortium

Properly controlled intestinal epithelial cell regeneration is not only vital for protection against insults from environmental hazards but also crucial for preventing intestinal cancer. Intestinal stem cells located in the crypt region provide the driving force for epithelial regeneration, and thus their survival and death must be precisely regulated. We show here that polypyrimidine tract binding protein 1 (PTBP1, also called heterogeneous nuclear ribonucleoprotein I, or HNRNP I), an RNA-binding protein that post-transcriptionally regulates gene expression, is critical for intestinal stem cell survival and stemness. Mechanistically, we show that PTBP1 inhibits the expression of PHLDA3, an AKT repressor, and thereby maintains AKT activity in the intestinal stem cell compartment to promote stem cell survival and proliferation. Furthermore, we show that PTBP1 inhibits the expression of PTBP2, a paralog of PTBP1 that is known to induce neuron differentiation, through repressing inclusion of alternative exon 10 to Ptbp2 transcript. Loss of PTBP1 results in a significant upregulation of PTBP2, which is accompanied by splicing changes in genes that are important for neuron cell development. This finding suggests that PTBP1 prevents aberrant differentiation of intestinal stem cells into neuronal cells through inhibiting PTBP2. Our results thus reveal a novel mechanism whereby PTBP1 maintains intestinal stem cell survival and stemness through the control of gene function post-transcriptionally.

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Modulation of Intestinal Stem Cell Homeostasis by Nutrients: A Novel Therapeutic Option for Intestinal Diseases

Nutrition Research Reviews ◽

10.1017/s0954422421000172 ◽

2021 ◽

pp. 1-28

Author(s):

Dan Wang ◽

Pei Li ◽

Jack Odle ◽

Xi Lin ◽

Jiangchao Zhao ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Nutrient Sensing ◽

Intestinal Stem Cells ◽

Intestinal Stem Cell ◽

Intestinal Epithelial ◽

Self Renewal ◽

Intestinal Diseases ◽

Epithelial Homeostasis ◽

Ketogenic Diets

Abstract Intestinal stem cells, which are capable of both self-renewal and differentiation to mature cell types, are responsible for maintaining intestinal epithelial homeostasis. Recent evidence indicates that these processes are mediated, in part, through nutritional status in response to diet. Diverse dietary patterns including caloric restriction, fasting, high-fat diets, ketogenic diets and high-carbohydrate diets as well as other nutrients control intestinal stem cell self-renewal and differentiation through nutrient-sensing pathways such as mTOR and AMPK. Herein, we summarize the current understanding of how intestinal stem cells contribute to intestinal epithelial homeostasis and diseases. We also discuss the effects of diet and nutrient-sensing pathways on intestinal stem cell self-renewal and differentiation, as well as their potential application in the prevention and treatment of intestinal diseases.

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Faculty Opinions recommendation of The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10883956.12086056 ◽

2011 ◽

Author(s):

Kim Jensen ◽

Robert Fordham

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Intestinal Stem Cell ◽

Disease Relapse ◽

Colorectal Cancer Stem Cells

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Macrophage-derived EDA-A2 inhibits intestinal stem cells by targeting miR-494/EDA2R/β-catenin signaling in mice

Communications Biology ◽

10.1038/s42003-021-01730-0 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Lele Song ◽

Renxu Chang ◽

Xia Sun ◽

Liying Lu ◽

Han Gao ◽

...

Keyword(s):

Stem Cell ◽

Cross Talk ◽

Intestinal Inflammation ◽

Intestinal Stem Cells ◽

Intestinal Stem Cell ◽

Epithelial Barrier ◽

Self Renewal ◽

Epithelial Repair ◽

Inflammatory Bowel

AbstractThe mucosa microenvironment is critical for intestinal stem cell self-renewal and reconstruction of the epithelial barrier in inflammatory bowel disease (IBD), where the mechanisms underlying cross-talk between intestinal crypts and the microenvironment remain unclear. Here, we firstly identified miR-494-3p as an important protector in colitis. miR-494-3p levels were decreased and negatively correlated with the severity in human IBD samples, as well as in colitis mice. In colitis crypts, a notable cytokine–cytokine receptor, miR-494-3p-targeted EDA2R and the ligand EDA-A2, suppressed colonic stemness and epithelial repair by inhibiting β-catenin/c-Myc. In differentiated IECs, miR-494-3p inhibits macrophage recruitment, M1 activation and EDA-A2 secretion by targeting IKKβ/NF-κB in colitis. A miR-494-3p agomir system notably ameliorated the severity of colonic colitis in vivo. Collectively, our findings uncover a miR-494-3p-mediated cross-talk mechanism by which macrophage-induced intestinal stem cell impairment aggravates intestinal inflammation.

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Circadian Regulation of Mitochondrial Uncoupling and Lifespan

Innovation in Aging ◽

10.1093/geroni/igaa057.2648 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 740-741

Author(s):

Matthew Ulgherait

Keyword(s):

Stem Cells ◽

Circadian Rhythm ◽

Uncoupling Protein ◽

Intestinal Stem Cells ◽

Intestinal Stem Cell ◽

Cellular Respiration ◽

Circadian Regulation ◽

Lifespan Extension ◽

Diet Restriction ◽

Mitochondrial Uncoupling

Abstract Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways, but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, up-regulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents over-proliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target.

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Immunostaining of Lgr5, an Intestinal Stem Cell Marker, in Normal and Premalignant Human Gastrointestinal Tissue

The Scientific World JOURNAL ◽

10.1100/tsw.2008.148 ◽

2008 ◽

Vol 8 ◽

pp. 1168-1176 ◽

Cited By ~ 76

Author(s):

Laren Becker ◽

Qin Huang ◽

Hiroshi Mashimo

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Niche ◽

Intestinal Stem Cells ◽

Stem Cell Marker ◽

Tumor Initiating Cells ◽

Colonic Adenomas ◽

Potential Marker ◽

Cell Niche ◽

Crypt Base

Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barrett's esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.

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Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO

Molecular Biology of the Cell ◽

10.1091/mbc.e19-10-0560 ◽

2020 ◽

Vol 31 (14) ◽

pp. 1538-1549

Author(s):

Fan Zhang ◽

Mehdi Pirooznia ◽

Hong Xu

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Transcription Factor ◽

Stem Cell ◽

Electron Transport Chain ◽

Intestinal Stem Cell ◽

Stem Cell Proliferation ◽

Epithelial Homeostasis ◽

Chain Complexes ◽

Transport Chain

Deficiencies in electron transport chain complexes increase the activity of FOXO transcription factor in Drosophila midgut stem cells, which impairs stem cell proliferation and enterocyte specification.

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Study on the Therapeutic Mechanism of LXGYD on Intestinal Stem Cells and Tight Junction Proteins in GI-ARS Rats

10.21203/rs.3.rs-1112710/v1 ◽

2021 ◽

Author(s):

Ziqiao Yan ◽

Bofeng Yin ◽

Yuguo Wang ◽

Jian Feng ◽

Qianyu Yang ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Health Status ◽

Tight Junction ◽

Western Blotting ◽

Rat Model ◽

Protective Efficacy ◽

Intestinal Stem Cells ◽

Pathological Analysis ◽

Chinese Herbal

Abstract Background: Gastrointestinal acute radiation injury syndrome (GI-ARS) is potentially lethal and may occur after exposure to high radiation doses. Various chemical and biological agents have been developed to treat GI-ARS. However, their clinical utility is limited as they induce serious adverse reactions at their effective doses. Chinese herbal medicines have attracted attention because of their protective efficacy and low toxicity in radiation exposure treatment. However, their cellular and molecular mechanisms remain unknown. Here, we investigated the effects of the Chinese herbal Liangxue-Guyuan-Yishen decoction (LXGYD) on the intestinal stem cells and signal pathways of a GI-ARS rat model. Currently, there are limited treatment methods available globally; LXGYD might be a potential therapeutic option for patients with GI-ARS. Methods: The rat GI-ARS model was prepared by whole-body irradiation with 10-Gy of 60Co-γ rays. Various LXGYD concentrations were intragastrically administered to the irradiated rats. Health status and survival of the rats were evaluated and the protective efficacy of LXGYD on the intestines was assayed by pathological analysis. The active principles in LXGYD were detected by liquid chromatography-mass spectrometry (LC-MS) and their potential targets and pathways were screened by network pharmacological analysis. Intestinal stem cell proliferation, intestinal epithelial tight junction (TJ) protein expression, and regulatory pathways were explored by immunohistochemistry (IHC), western blotting (WB), and real-time quantitative polymerase chain reaction (RT-qPCR), respectively.Results: LXGYD administration significantly improved health status and survival in GI-ARS rats. The pathological analysis showed that LXGYD ameliorated radiation-induced intestinal injury. The LXGYD infusion significantly promoted LGR5+ stem cell regeneration in the ileal crypts, upregulated TJ proteins, and accelerated crypt reconstruction in the irradiated rats in a dose-dependent manner. LC-MS revealed ≥ 13 LXGYD constituents that might contribute to its protective effects. Involvement of the WNT and MEK/ERK pathways in intestinal repair and recovery were screened by network pharmacology analysis and validated by western blotting.Conclusions: The present study disclosed a heretofore unrecognized role of the Chinese herbal LXGYD in rescuing the intestinal stem cells of a GI-ARS rat model. It also showed that the WNT and MEK/ERK pathways may be involved in LXGYD-mediated intestinal regeneration in GI-ARS.

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Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01740-6 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Luciana Petti ◽

Giulia Rizzo ◽

Federica Rubbino ◽

Sudharshan Elangovan ◽

Piergiuseppe Colombo ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cell Proliferation ◽

Stem Cell ◽

Tumor Suppressor ◽

Normal Mucosa ◽

Intestinal Stem Cells ◽

Intestinal Epithelial ◽

Sphingosine 1 Phosphate

Abstract Background Sphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap. Methods We screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2+/+) and S1PR2 deficient (S1PR2−/−) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked the ablation of S1PR2 in normal mucosa by treating S1PR2+/+ organoids with JTE013 and characterized intestinal epithelial stem cells isolated from S1PR2−/−Lgr5-EGFP- mice. Results S1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc+/min mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2−/− mice compared to S1PR2+/+ controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN. Conclusions In normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5. Graphical Abstract. Schematic drawing of the role of S1PR2 in normal mucosa and colorectal cancer. In the normal mucosa, S1PR2 is highly expressed by differentiated cells at the upper region of both colon and intestinal crypts (S1PR2 ON), but not by the undifferentiated stem cell at the base of the crypts (S1PR2 OFF), in which acts as a negative proliferative regulator promoting epithelial differentiation. Its loss leads to the expansion of stem cells and reduced levels of PTEN and Axin-2, two negative regulators respectively of PI3K/AKT and Wnt signaling that control β-catenin signaling. The translocation of β-catenin into the nucleus promotes the transcription of target genes involved in the proliferation and malignant transformation. Thereby, S1PR2 works in the intestine as a tumor suppressor

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Confetti illuminates the cryptic way calorie restriction protects from cancer

Science Translational Medicine ◽

10.1126/scitranslmed.abd4765 ◽

2020 ◽

Vol 12 (555) ◽

pp. eabd4765

Author(s):

Emily J. Gallagher

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Calorie Restriction ◽

Intestinal Stem Cell ◽

Cell Competition

Calorie restriction increases intestinal stem cell competition and decreases the retention of stem cells with mutations in mice.

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