scholarly journals Loss of Slfn3 induces a gender-dependent repair vulnerability after 50% bowel resection

2020 ◽  
Author(s):  
Emilie Erin Vomhof-DeKrey ◽  
Jack T Lansing ◽  
Diane C Darland ◽  
Josey Umthun ◽  
Allie D Stover ◽  
...  
Keyword(s):  
Bowel Resection ◽  
Intestinal Adaptation ◽  
Functional Differentiation ◽  
Differentiation Markers ◽  
Proliferation Markers ◽  
Crypt Depth ◽  
Enterocyte Proliferation ◽  
Important Regulator ◽  
Cell Shedding ◽  
Enterocytic Differentiation

Bowel resection accelerates enterocyte proliferation in the remaining gut that may have suboptimal absorptive and digestive capacity because of proliferation-associated decrease in functional differentiation markers. We hypothesized that although Slfn3 is an important regulator of murine enterocytic differentiation, Slfn3 would have less impact on the bowel resection adaptation where accelerated proliferation takes priority over differentiation. We assessed proliferation, cell shedding, and enterocyte differentiation markers of mucosa from resected and postoperative bowel of wild type (WT) and Slfn3 knockout (Slfn3KO) mice. Villus length and crypt depth were increased in WT mice and was even longer in Slfn3KO mice, while female Slfn3KO mice displayed even deeper crypts than both WT sexes after resection. Mitotic marker, Phh3+, and proliferation marker expression of Lgr5, FoxL1, and PDGFRα were increased after resection in male WT but this effect was blunted in male Slfn3KO mice. Cell shedding regulators Villin1 and TNFα were downregulated in female mice and male WT mice only, while Gelsolin and EGFR increased expression in all mice. Slfn3 expression increased after resection in WT mice but differentiation markers sucrase isomaltase, Dpp4, Glut2, and SGLT1 were all decreased. This suggests that enterocytic differentiation effort is incompatible with a rapid proliferation shift in intestinal adaptation. Slfn3 absence potentiates villus length and crypt depth, suggesting that the differentiating stimulus of Slfn3 signaling may restrain mucosal mass increase through regulating Villin1, Gelsolin, EGFR, TNFα, and proliferation markers. Slfn3 may therefore be an important regulator not only of "normal" enterocytic differentiation but also the response to bowel resection.

Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection

2003 ◽  
Vol 284 (4) ◽  
pp. G670-G682 ◽  
Author(s):  
Elizabeth M. Dahly ◽  
Melanie B. Gillingham ◽  
Ziwen Guo ◽  
Sangita G. Murali ◽  
David W. Nelson ◽  
...  
Keyword(s):  
Small Bowel ◽  
Adaptive Response ◽  
Bowel Resection ◽  
Intestinal Adaptation ◽  
Small Bowel Resection ◽  
Oral Feeding ◽  
Enterocyte Proliferation ◽  
Glucagon Like Peptide ◽  
Mucosal Growth

To elucidate the role of luminal nutrients and glucagon-like peptide-2 (GLP-2) in intestinal adaptation, rats were subjected to 70% midjejunoileal resection or ileal transection and were maintained with total parenteral nutrition (TPN) or oral feeding. TPN rats showed small bowel mucosal hyperplasia at 8 h through 7 days after resection, demonstrating that exogenous luminal nutrients are not essential for resection-induced adaptation when residual ileum and colon are present. Increased enterocyte proliferation was a stronger determinant of resection-induced mucosal growth in orally fed animals, whereas decreased apoptosis showed a greater effect in TPN animals. Resection induced significant transient increases in plasma bioactive GLP-2 during TPN, whereas resection induced sustained increases in plasma GLP-2 during oral feeding. Resection-induced adaptive growth in TPN and orally fed rats was associated with a significant positive correlation between increases in plasma bioactive GLP-2 and proglucagon mRNA expression in the colon of TPN rats and ileum of orally fed rats. These data support a significant role for endogenous GLP-2 in the adaptive response to mid-small bowel resection in both TPN and orally fed rats.

scholarly journals Ret heterozygous mice have enhanced intestinal adaptation after massive small bowel resection

2012 ◽  
Vol 302 (10) ◽  
pp. G1143-G1150 ◽  
Author(s):  
Meredith C. Hitch ◽  
Jennifer A. Leinicke ◽  
Derek Wakeman ◽  
Jun Guo ◽  
Chris R. Erwin ◽  
...  
Keyword(s):  
Small Bowel ◽  
Bowel Resection ◽  
Intestinal Adaptation ◽  
Growth Factor Receptor ◽  
Small Bowel Resection ◽  
Compensatory Response ◽  
Protein Levels ◽  
Enterocyte Proliferation ◽  
Glucagon Like Peptide ◽  
Massive Small Bowel Resection

Intestinal adaptation is an important compensatory response to massive small bowel resection (SBR) and occurs because of a proliferative stimulus to crypt enterocytes by poorly understood mechanisms. Recent studies suggest the enteric nervous system (ENS) influences enterocyte proliferation. We, therefore, sought to determine whether ENS dysfunction alters resection-induced adaptation responses. Ret+/− mice with abnormal ENS function and wild-type (WT) littermates underwent sham surgery or 50% SBR. After 7 days, ileal morphology, enterocyte proliferation, apoptosis, and selected signaling proteins were characterized. Crypt depth and villus height were equivalent at baseline in WT and Ret+/− mice. In contrast after SBR, Ret+/− mice had longer villi (Ret+/− 426.7 ± 46.0 μm vs. WT 306.5 ± 7.7 μm, P < 0.001) and deeper crypts (Ret+/− 119 ± 3.4 μm vs. WT 82.4 ± 3.1 μm, P < 0.001) than WT. Crypt enterocyte proliferation was higher in Ret+/− (48.8 ± 1.3%) than WT (39.9 ± 2.1%; P < 0.001) after resection, but apoptosis rates were similar. Remnant bowel of Ret+/− mice also had higher levels of glucagon-like peptide 2 (6.2-fold, P = 0.005) and amphiregulin (4.6-fold, P < 0.001) mRNA after SBR, but serum glucagon-like peptide 2 protein levels were equal in WT and Ret+/− mice, and there was no evidence of increased c-Fos nuclear localization in submucosal neurons. Western blot confirmed higher crypt epidermal growth factor receptor (EGFR) protein levels (1.44-fold; P < 0.001) and more phosphorylated EGFR (2-fold; P = 0.003) in Ret+/− than WT mice after SBR. These data suggest that Ret heterozygosity enhances intestinal adaptation after massive SBR, likely via enhanced EGFR signaling. Reducing Ret activity or altering ENS function may provide a novel strategy to enhance adaptation attenuating morbidity in patients with short bowel syndrome.

Intestinal adaptation and enterocyte apoptosis following small bowel resection is p53 independent

1999 ◽  
Vol 277 (3) ◽  
pp. G717-G724 ◽  
Author(s):  
Cathy E. Shin ◽  
Richard A. Falcone ◽  
Christopher J. Kemp ◽  
Christopher R. Erwin ◽  
David A. Litvak ◽  
...  
Keyword(s):  
Small Bowel ◽  
Protein Content ◽  
Bowel Resection ◽  
Intestinal Adaptation ◽  
Small Bowel Resection ◽  
Apoptotic Bodies ◽  
Wild Type ◽  
Villus Height ◽  
Enterocyte Proliferation ◽  
Enterocyte Apoptosis

Adaptation following small bowel resection (SBR) signals enterocyte proliferation and apoptosis. Because p53-induced p21waf1/cip1may be important for apoptosis in many cells, we hypothesized that these genes are required for increased enterocyte apoptosis during adaptation. Male C57BL/6 (wild-type) or p53-null mice underwent 50% proximal SBR or sham operation (bowel transection-reanastomosis). Adaptation (DNA-protein content, villus height-crypt depth, enterocyte proliferation), appearance of apoptotic bodies, and p53 and p21waf1/cip1protein expression were measured in the ileum after 5 days. Adaptation was equivalent after SBR in both wild-type and p53-null mice as monitored by significantly increased ileal DNA-protein content, villus height, and enterocyte proliferation. The number of crypt apoptotic bodies increased significantly after SBR evenly in both wild-type and p53-null mice. In the p53-null mice, SBR substantially induced the expression of p21waf1/cip1protein in villus enterocytes. The p53-independent induction of p21waf1/cip1may account for the similar intestinal response to SBR between wild-type and p53-null mice. Intestinal adaptation and increased enterocyte apoptosis following intestinal resection occur via a p53-independent mechanism.

Gut adaptation and the insulin-like growth factor system: regulation by glutamine and IGF-I administration

1996 ◽  
Vol 271 (5) ◽  
pp. G866-G875 ◽  
Author(s):  
T. R. Ziegler ◽  
M. P. Mantell ◽  
J. C. Chow ◽  
J. L. Rombeau ◽  
R. J. Smith
Keyword(s):  
Growth Factor ◽  
Small Bowel ◽  
Dna Content ◽  
Bowel Resection ◽  
Synergistic Effects ◽  
Intestinal Adaptation ◽  
Intestinal Resection ◽  
Small Bowel Resection ◽  
Insulin Like Growth Factor ◽  
Igf I

Intestinal adaptation after extensive small bowel resection in rats is augmented by the provision of diets supplemented with the amino acid glutamine (Gln) or by administration of insulin-like growth factor-I (IGF-I). The goal of this study was to investigate potential synergistic effects of Gln and IGF-I on postresection ileal hyperplasia. Rats underwent 80% small bowel resection (SBR) and then were fed low-Gln or L-Gln-enriched diets and subcutaneously given recombinant human IGF-I or vehicle for 7 days. Gln and IGF-I each significantly enhanced adaptive ileal hyperplasia (DNA content) compared with rats receiving vehicle and low-Gln diet. Ileal DNA content was highest when IGF-I was administered together with Gln supplementation. Combined IGF-I plus Gln synergistically increased ileal weight and protein content. This was associated with higher plasma concentrations of IGF-I and Gln than observed when IGF-I or Gln was given individually. Ileal IGF-I mRNA expression rose nearly twofold during gut adaptation after SBR; this response was augmented with IGF-I administration but was unaltered by Gln feeding. In contrast, dietary Gln, but not IGF-I therapy, prevented a decrease in hepatic IGF-I mRNA induced by SBR. We conclude that parenteral IGF-I and enteral Gln have both individual and synergistic effects on ileal adaptation after massive small intestinal resection. These findings support the concept that specific gut-trophic nutrients and growth factors may be combined to enhance intestinal adaptation and possibly reduce the severity of short bowel syndrome after intestinal resection.

p21 is elevated and intestinal adaptation is preserved in p27-null mice following small bowel resection

2003 ◽  
Vol 124 (4) ◽  
pp. A600
Author(s):  
Rusell J. Juno ◽  
Andrew W. Knott ◽  
Marcus D. Jarboe ◽  
Christopher R. Erwin ◽  
Brad W. Warner
Keyword(s):  
Small Bowel ◽  
Bowel Resection ◽  
Intestinal Adaptation ◽  
Small Bowel Resection

scholarly journals Cooperation between HNF-1α, Cdx2, and GATA-4 in initiating an enterocytic differentiation program in a normal human intestinal epithelial progenitor cell line

2010 ◽  
Vol 298 (4) ◽  
pp. G504-G517 ◽  
Author(s):  
Yannick D. Benoit ◽  
Fréderic Paré ◽  
Caroline Francoeur ◽  
Dominique Jean ◽  
Eric Tremblay ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Line ◽  
Large Scale ◽  
Morphological Changes ◽  
Ectopic Expression ◽  
Functional Differentiation ◽  
Stem Cell Markers ◽  
Intestinal Epithelial ◽  
Differentiation Markers ◽  
Functional Features

In the intestinal epithelium, the Cdx, GATA, and HNF transcription factor families are responsible for the expression of differentiation markers such as sucrase-isomaltase. Although previous studies have shown that Cdx2 can induce differentiation in rat intestinal IEC-6 cells, no data are available concerning the direct implication of transcription factors on differentiation in human normal intestinal epithelial cell types. We investigated the role of Cdx2, GATA-4, and HNF-1α using the undifferentiated human intestinal epithelial crypt cell line HIEC. These transcription factors were tested on proliferation and expression of polarization and differentiation markers. Ectopic expression of Cdx2 or HNF-1α, alone or in combination, altered cell proliferation abilities through the regulation of cyclin D1 and p27 expression. HNF-1α and GATA-4 together induced morphological modifications of the cells toward polarization, resulting in the appearance of functional features such as microvilli. HNF-1α was also sufficient to induce the expression of cadherins and dipeptidylpeptidase, whereas in combination with Cdx2 it allowed the expression of the late differentiation marker sucrase-isomaltase. Large-scale analysis of gene expression confirmed the cooperative effect of these factors. Finally, although DcamKL1 and Musashi-1 expression were downregulated in differentiated HIEC, other intestinal stem cell markers, such as Bmi1, were unaffected. These observations show that, in cooperation with Cdx2, HNF-1α acts as a key factor on human intestinal cells to trigger the onset of their functional differentiation program whereas GATA-4 appears to promote morphological changes.

scholarly journals A Novel AURKA Mutant-Induced Early-Onset Severe Hepatocarcinogenesis Greater than Wild-Type via Activating Different Pathways in Zebrafish

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 927 ◽  
Author(s):  
Zhong-Liang Su ◽  
Chien-Wei Su ◽  
Yi-Luen Huang ◽  
Wan-Yu Yang ◽  
Bonifasius Putera Sampurna ◽  
...  
Keyword(s):  
Early Onset ◽  
Transgenic Fish ◽  
Aurora A Kinase ◽  
Mitotic Progression ◽  
Wild Type ◽  
Proliferation Markers ◽  
Long Latency ◽  
Important Regulator ◽  
Low Incidence ◽  
Screening Platform

Aurora A kinase (AURKA) is an important regulator in mitotic progression and is overexpressed frequently in human cancers, including hepatocellular carcinoma (HCC). Many AURKA mutations were identified in cancer patients. Overexpressing wild-type Aurka developed a low incidence of hepatic tumors after long latency in mice. However, none of the AURKA mutant animal models have ever been described. The mechanism of mutant AURKA-mediated hepatocarcinogenesis is still unclear. A novel AURKA mutation with a.a.352 Valine to Isoleucine (V352I) was identified from clinical specimens. By using liver-specific transgenic fish overexpressing both the mutant and wild-type AURKA, the AURKA(V352I)-induced hepatocarcinogenesis was earlier and much more severe than wild-type AURKA. Although an increase of the expression of lipogenic enzyme and lipogenic factor was observed in both AURKA(V352I) and AURKA(WT) transgenic fish, AURKA(V352I) has a greater probability to promote fibrosis at 3 months compared to AURKA(WT). Furthermore, the expression levels of cell cycle/proliferation markers were higher in the AURKA(V352I) mutant than AURKA(WT) in transgenic fish, implying that the AURKA(V352I) mutant may accelerate HCC progression. Moreover, we found that the AURKA(V352I) mutant activates AKT signaling and increases nuclear β-catenin, but AURKA(WT) only activates membrane form β-catenin, which may account for the differences. In this study, we provide a new insight, that the AURKA(V352I) mutation contributes to early onset hepatocarcinogenesis, possibly through activation of different pathways than AURKA(WT). This transgenic fish may serve as a drug-screening platform for potential precision medicine therapeutics.

scholarly journals Cluster Analysis of p53 Binding Site Sequences Reveals Subsets with Different Functions

2016 ◽  
Vol 15 ◽  
pp. CIN.S39968
Author(s):  
Ji-Hyun Lim ◽  
Natasha S. Latysheva ◽  
Richard D. Iggo ◽  
Daniel Barker
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
P53 Protein ◽  
Species Conservation ◽  
Structural Data ◽  
Functional Differentiation ◽  
Dna Binding Domain ◽  
Response Elements ◽  
Cycle Arrest ◽  
Important Regulator

p53 is an important regulator of cell cycle arrest, senescence, apoptosis and metabolism, and is frequently mutated in tumors. It functions as a tetramer, where each component dimer binds to a decameric DNA region known as a response element. We identify p53 binding site subtypes and examine the functional and evolutionary properties of these subtypes. We start with over 1700 known binding sites and, with no prior labeling, identify two sets of response elements by unsupervised clustering. When combined, they give rise to three types of p53 binding sites. We find that probabilistic and alignment-based assessments of cross-species conservation show no strong evidence of differential conservation between types of binding sites. In contrast, functional analysis of the genes most proximal to the binding sites provides strong bioinformatic evidence of functional differentiation between the three types of binding sites. Our results are consistent with recent structural data identifying two conformations of the L1 loop in the DNA binding domain, suggesting that they reflect biologically meaningful groups imposed by the p53 protein structure.

Mechanobiology of bone cells

2010 ◽  
Vol 19 (03) ◽  
pp. 245-249
Author(s):  
J. Rychly
Keyword(s):  
Binding Sites ◽  
Bone Cells ◽  
Mechanical Forces ◽  
Integrin Receptors ◽  
Differentiation Markers ◽  
Bone Material ◽  
Adhesion Sites ◽  
Important Regulator ◽  
Biochemical Signals ◽  
Stimulation Of

SummaryBone mass, morphology and properties of the bone material are regulated by the functions of osteoblasts, osteocytes, and osteoclasts. These cells respond directly or indirectly to mechanical forces from the environment with the expression of differentiation markers, proliferation or release of bioactive factors. Osteocytes appear to be an important regulator for the adaptation of bone to changes in the mechanical environment. Mesenchymal stem cells which are located in bone marrow can be mechanically stimulated to differentiate into osteoblasts and chondrocytes but not to adipocytes. Integrin receptors are the principal mediators of mechanical forces and induce a signal transduction. The conversion of mechanical signals into biochemical signals is facilitated by unfolding of proteins to expose binding sites. Implant materials offer the opportunity to control the mechanical stimulation of cells by modifying the rigidity, geometry of adhesion sites, and the 3D-environment.

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