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

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.

scholarly journals PTBP1/HNRNP I controls intestinal epithelial cell regeneration by maintaining stem cell survival and stemness

2021 ◽  
Author(s):  
Wesley Tung ◽  
Ullas Valiya Chembazhi ◽  
Jing Yang ◽  
Ka Lam Nguyen ◽  
Aryan Lalwani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Epithelial Cell ◽  
Cell Survival ◽  
Intestinal Epithelial Cell ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell ◽  
Cell Regeneration ◽  
Intestinal Epithelial ◽  
Stem Cell Survival

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.

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

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.

scholarly journals Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO

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.

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

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

scholarly journals Intestinal stem cells and stem cell-based therapy for intestinal diseases

2014 ◽  
Vol 67 (2) ◽  
pp. 177-189 ◽  
Author(s):  
Mahmoud Shaaban Mohamed ◽  
Yun Chen ◽  
Chao-Ling Yao
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Intestinal Stem Cells ◽  
Intestinal Diseases ◽  
Cell Based Therapy

scholarly journals Essential role for autophagy protein ATG7 in the maintenance of intestinal stem cell integrity

2020 ◽  
Vol 117 (20) ◽  
pp. 11136-11146 ◽  
Author(s):  
Coralie Trentesaux ◽  
Marie Fraudeau ◽  
Caterina Luana Pitasi ◽  
Julie Lemarchand ◽  
Sébastien Jacques ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Intestinal Epithelium ◽  
Tumor Formation ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell ◽  
Intestinal Epithelial ◽  
Cell Integrity ◽  
Autophagy Gene ◽  
Defective Dna Repair

The intestinal epithelium acts as a barrier between the organism and its microenvironment, including the gut microbiota. It is the most rapidly regenerating tissue in the human body thanks to a pool of intestinal stem cells (ISCs) expressing Lgr5. The intestinal epithelium has to cope with continuous stress linked to its digestive and barrier functions. Epithelial repair is crucial to maintain its integrity, and Lgr5-positive intestinal stem cell (Lgr5+ISC) resilience following cytotoxic stresses is central to this repair stage. We show here that autophagy, a pathway allowing the lysosomal degradation of intracellular components, plays a crucial role in the maintenance and genetic integrity of Lgr5+ISC under physiological and stress conditions. Using conditional mice models lacking the autophagy gene Atg7 specifically in all intestinal epithelial cells or in Lgr5+ISC, we show that loss of Atg7 induces the p53-mediated apoptosis of Lgr5+ISC. Mechanistically, this is due to increasing oxidative stress, alterations to interactions with the microbiota, and defective DNA repair. Following irradiation, we show that Lgr5+ISC repair DNA damage more efficiently than their progenitors and that this protection is Atg7 dependent. Accordingly, we found that the stimulation of autophagy on fasting protects Lgr5+ISC against DNA damage and cell death mediated by oxaliplatin and doxorubicin treatments. Finally, p53 deletion prevents the death of Atg7-deficient Lgr5+ISC but promotes genetic instability and tumor formation. Altogether, our findings provide insights into the mechanisms underlying maintenance and integrity of ISC and highlight the key functions of Atg7 and p53.

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

2019 ◽  
Vol 316 (2) ◽  
pp. G247-G250
Author(s):  
Timothy C. Wang ◽  
Martin G. Martin ◽  
Calvin J. Kuo ◽  
Ophir D. Klein ◽  
Joyce Niland
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell

scholarly journals Arid1a is essential for intestinal stem cells through Sox9 regulation

2019 ◽  
Vol 116 (5) ◽  
pp. 1704-1713 ◽  
Author(s):  
Yukiko Hiramatsu ◽  
Akihisa Fukuda ◽  
Satoshi Ogawa ◽  
Norihiro Goto ◽  
Kozo Ikuta ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Functional Role ◽  
Molecular Mechanisms ◽  
Intestinal Epithelial Cells ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Intestinal Homeostasis ◽  
Self Renewal

Inactivating mutations of Arid1a, a subunit of the Switch/sucrose nonfermentable chromatin remodeling complex, have been reported in multiple human cancers. Intestinal deletion of Arid1a has been reported to induce colorectal cancer in mice; however, its functional role in intestinal homeostasis remains unclear. We investigated the functional role of Arid1a in intestinal homeostasis in mice. We found that intestinal deletion of Arid1a results in loss of intestinal stem cells (ISCs), decreased Paneth and goblet cells, disorganized crypt-villous structures, and increased apoptosis in adult mice. Spheroids did not develop from intestinal epithelial cells deficient for Arid1a. Lineage-tracing experiments revealed that Arid1a deletion in Lgr5+ ISCs leads to impaired self-renewal of Lgr5+ ISCs but does not perturb intestinal homeostasis. The Wnt signaling pathway, including Wnt agonists, receptors, and target genes, was strikingly down-regulated in Arid1a-deficient intestines. We found that Arid1a directly binds to the Sox9 promoter to support its expression. Remarkably, overexpression of Sox9 in intestinal epithelial cells abrogated the above phenotypes, although Sox9 overexpression in intestinal epithelial cells did not restore the expression levels of Wnt agonist and receptor genes. Furthermore, Sox9 overexpression permitted development of spheroids from Arid1a-deficient intestinal epithelial cells. In addition, deletion of Arid1a concomitant with Sox9 overexpression in Lgr5+ ISCs restores self-renewal in Arid1a-deleted Lgr5+ ISCs. These results indicate that Arid1a is indispensable for the maintenance of ISCs and intestinal homeostasis in mice. Mechanistically, this is mainly mediated by Sox9. Our data provide insights into the molecular mechanisms underlying maintenance of ISCs and intestinal homeostasis.

scholarly journals Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Bo Li ◽  
Carol Lee ◽  
Marissa Cadete ◽  
Haitao Zhu ◽  
Yuhki Koike ◽  
...  
Keyword(s):  
Stem Cell ◽  
Necrotizing Enterocolitis ◽  
Intestinal Injury ◽  
Acute Injury ◽  
Intestinal Stem Cell ◽  
Intestinal Epithelial ◽  
Neonatal Disease ◽  
Epithelial Homeostasis ◽  
Intestinal Regeneration ◽  
Intestinal Organoids

Abstract Necrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by acute intestinal injury. Intestinal stem cell (ISC) renewal is required for gut regeneration in response to acute injury. The Wnt/β-catenin pathway is essential for intestinal renewal and ISC maintenance. We found that ISC expression, Wnt activity and intestinal regeneration were all decreased in both mice with experimental NEC and in infants with acute active NEC. Moreover, intestinal organoids derived from NEC-injured intestine of both mice and humans failed to maintain proliferation and presented more differentiation. Administration of Wnt7b reversed these changes and promoted growth of intestinal organoids. Additionally, administration of exogenous Wnt7b rescued intestinal injury, restored ISC, and reestablished intestinal epithelial homeostasis in mice with NEC. Our findings demonstrate that during NEC, Wnt/β-catenin signaling is decreased, ISC activity is impaired, and intestinal regeneration is defective. Administration of Wnt resulted in the maintenance of intestinal epithelial homeostasis and avoidance of NEC intestinal injury.

scholarly journals Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate

2021 ◽  
Author(s):  
Laura García-Prat ◽  
Kerstin B. Kaufmann ◽  
Florin Schneiter ◽  
Veronique Voisin ◽  
Alex Murison ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Nutrient Sensing ◽  
Cell Fate Determination ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stem Cell Fate ◽  
Transcription Factor Eb

SummaryIt is critical to understand how quiescent long-term hematopoietic stem cells (LT-HSC) sense demand from daily and stress-mediated cues and transition into bioenergetically active progeny to differentiate and meet these cellular needs. Here, we show that lysosomes, which are sophisticated nutrient sensing and signaling centers, are dichotomously regulated by the Transcription Factor EB (TFEB) and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway causes membrane receptor degradation, limiting LT-HSC metabolic and mitogenic activation, which promotes quiescence, self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

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