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 Mitochondrial Metabolism in the Intestinal Stem Cell Niche—Sensing and Signaling in Health and Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Elisabeth Urbauer ◽  
Eva Rath ◽  
Dirk Haller
Keyword(s):  
Stem Cell ◽  
Epithelial Cell ◽  
Mitochondrial Function ◽  
Stem Cell Niche ◽  
Intestinal Epithelial Cell ◽  
Mitochondrial Metabolism ◽  
Intestinal Stem Cell ◽  
Intestinal Epithelial ◽  
Health And Disease ◽  
Cell Niche

Mitochondrial metabolism, dynamics, and stress responses in the intestinal stem cell niche play a pivotal role in regulating intestinal epithelial cell homeostasis, including self-renewal and differentiation. In addition, mitochondria are increasingly recognized for their involvement in sensing the metabolic environment and their capability of integrating host and microbial-derived signals. Gastrointestinal diseases such as inflammatory bowel diseases and colorectal cancer are characterized by alterations of intestinal stemness, the microbial milieu, and mitochondrial metabolism. Thus, mitochondrial function emerges at the interface of determining health and disease, and failure to adapt mitochondrial function to environmental cues potentially results in aberrant tissue responses. A mechanistic understanding of the underlying role of mitochondrial fitness in intestinal pathologies is still in its infancy, and therapies targeting mitochondrial (dys)function are currently lacking. This review discusses mitochondrial signaling and metabolism in intestinal stem cells and Paneth cells as critical junction translating host- and microbe-derived signals into epithelial responses. Consequently, we propose mitochondrial fitness as a hallmark for intestinal epithelial cell plasticity, determining the regenerative capacity of the epithelium.

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 The ARTS of Cell Death

2019 ◽  
Vol 12 ◽  
pp. 117906601983696 ◽  
Author(s):  
Elle Koren ◽  
Yaron Fuchs
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Cell Survival ◽  
Intestinal Stem Cell ◽  
Inhibitor Of Apoptosis ◽  
Self Renewal ◽  
The Arts ◽  
Apoptotic Protein ◽  
Stem Cell Survival ◽  
Dependent Processes

Although much is known regarding intestinal stem cell (ISC) self-renewal and differentiation, the specific mechanisms used for their elimination is unclear. We recently discovered that the pro-apoptotic protein ARTS, a Septin4 isoform, interacts with X-linked inhibitor of apoptosis (XIAP) in the ISC niche to regulate stem cell survival during intestinal homeostasis and regeneration. These findings point to an intriguing avenue of translational research, examining how manipulation of stem cell apoptosis through the ARTS/XIAP module can affect stem-cell-dependent processes.

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 epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis

2018 ◽  
Vol 315 (4) ◽  
pp. E638-E649 ◽  
Author(s):  
Yu Zheng ◽  
Yongli Song ◽  
Qi Han ◽  
Wenjie Liu ◽  
Jiuzhi Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
High Throughput Sequencing ◽  
Secretory Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Microbial Composition ◽  
Epithelial Regeneration

It is well known that insulin-like growth factor 1 (IGF1) acts as a trophic factor in small intestine under both physiological and pathophysiological conditions. However, it still lacks direct in vivo evidence of the functions of intestinal epithelial cell (IEC)-specific IGF1 under both normal and pathological conditions. Using IEC-specific IGF1-knockout (cKO) mice and Lgr5-eGFP-CreERT mice, we demonstrate that IEC-specific IGF1 can enhance nutrient uptake, reduce protein catabolism and energy consumption, and promote the proliferation and expansion of intestinal epithelial cells, including intestinal epithelial stem cells and intestinal secretory cells. Next, we showed that IEC-specific IGF1 renders IECs resistant to irradiation and promotes epithelial regeneration. Strikingly, transcriptome profiling assay revealed that many differentially expressed genes involved in the differentiation and maturation of lymphoid lineages were significantly suppressed in the cKO mice as compared with the control mice. We demonstrated that deletion of IGF1 in IECs enhances bacterial translocation to the mesenteric lymph nodes and liver. Furthermore, high-throughput sequencing of 16S ribosomal RNA genes of gut microbiota revealed that IEC-specific IGF1 loss profoundly affected the gut microbial composition at various levels of classification. Therefore, our findings shed light on the in vivo roles of IEC-specific IGF1 in intestinal homeostasis, epithelial regeneration, and immunity, broadening our current insights on IGF1 functions.

Human intestinal epithelial cell survival: differentiation state-specific control mechanisms

2001 ◽  
Vol 280 (6) ◽  
pp. C1540-C1554 ◽  
Author(s):  
Rémy Gauthier ◽  
Charlène Harnois ◽  
Jean-François Drolet ◽  
John C. Reed ◽  
Anne Vézina ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Cell Survival ◽  
Intestinal Epithelial Cell ◽  
The State ◽  
Control Mechanisms ◽  
Intestinal Epithelial ◽  
Human Intestinal Epithelial Cell ◽  
Expression Levels ◽  
Specific Control

To investigate whether human intestinal epithelial cell survival involves distinct control mechanisms depending on the state of differentiation, we analyzed the in vitro effects of insulin, pharmacological inhibitors of Fak, MEK/Erk, and PI3-K/Akt, and integrin (β1, β4)-blocking antibodies on the survival of the well-established human Caco-2 enterocyte-like and HIEC-6 cryptlike cell models. In addition, relative expression levels of six Bcl-2 homologs (Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and Bad) and activation levels of Fak, Erk-2, and Akt were analyzed. Herein, we report that 1) the enterocytic differentiation process results in the establishment of distinct profiles of Bcl-2 homolog expression levels, as well as p125Fak, p42Erk-2, and p57Aktactivated levels; 2) the inhibition of Fak, of the MEK/Erk pathway, or of PI3-K, have distinct impacts on enterocytic cell survival in undifferentiated (subconfluent Caco-2, confluent HIEC-6) and differentiated (30 days postconfluent Caco-2) cells; 3) exposure to insulin and the inhibition of Fak, MEK, and PI3-K resulted in differentiation state-distinct modulations in the expression of each Bcl-2 homolog analyzed; and 4) Fak, β1 and β4 integrins, as well as the MEK/Erk and PI3-K/Akt pathways, are distinctively involved in cell survival depending on the state of cell differentiation. Taken together, these data indicate that human intestinal epithelial cell survival is regulated according to differentiation state-specific control mechanisms.

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