Epimorphin deletion inhibits polyposis in theApcmin/+mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion

Swietlicki, Elzbieta A.; Bala, Shashi; Lü, Jianyun; Shaker, Anisa; Kularatna, Gowri; Levin, Marc S.; Rubin, Deborah C.

doi:10.1152/ajpgi.00486.2012

Cited by 6 publications

(12 citation statements)

References 38 publications

(67 reference statements)

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“…To verify that stromal cells were ISEMFs, cells were cultured on glass slides and fixed in formalin. Immunofluorescence analysis was performed (20,21) to detect smooth muscle ␣-actin (5694 rabbit polyclonal antibody, 1:200; Abcam), vimentin (8978, mouse monoclonal antibody, 1:50; Abcam), and desmin (15200, rabbit polyclonal antibody, 1:50; Abcam) expression. Anti-rabbit FITC, anti-mouse FITC, and anti-rabbit Cy3 were each used at 1:200 dilutions (Jackson ImmunoResearch Laboratories).…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, Epim Ϫ/Ϫ mice had reduced dysplasia in an azoxymethane/dextran sodium sulfate model of colitis-associated cancer, likely because of reduced epithelial damage and increased epithelial repair during colitis induction (20). Consistent with its role as a syntaxin, Epim regulates constitutive and stimulated secretion of selected growth factors from colon myofibroblasts (20).…”

Section: Introductionmentioning

confidence: 94%

“…ISEMFs support the growth of cocultured epithelial cells (11,20). To quantify the effect of ISEMFs on intestinal enteroid growth and budding, ISEMFs were isolated and cultured from mouse intestine as described (20,21) and as per MATERIALS AND METHODS.…”

Section: Coculture Of Isemfs With Enteroids Increases Enteroid Growthmentioning

confidence: 99%

“…In the dextran sodium sulfate-induced mouse colitis model, Epim Ϫ/Ϫ mice had increased injury-induced colonic crypt cell proliferation and reduced epithelial injury, likely because of enhanced epithelial repair (23). Similarly, Epim Ϫ/Ϫ mice had reduced dysplasia in an azoxymethane/dextran sodium sulfate model of colitis-associated cancer, likely because of reduced epithelial damage and increased epithelial repair during colitis induction (20). Consistent with its role as a syntaxin, Epim regulates constitutive and stimulated secretion of selected growth factors from colon myofibroblasts (20).…”

Section: Introductionmentioning

confidence: 96%

“…In the gut, in addition to Paneth cells, stromal cells such as intestinal subepithelial myofibroblasts (ISEMFs) are postulated to be important components of the niche, but their precise role and the requirement for mesenchymal cells for normal stem cell function are still being elucidated (1,9,11,22). To begin to understand the role of myofibroblasts in the stem cell niche, we have focused on examining the function of epimorphin (Epim, also known as syntaxin 2), a member of the syntaxin family of membranebound intracellular secretory vesicle docking proteins expressed in ISEMFS that play an important role in regulating cell secretion (4,7,20,21,23,25). We have previously shown that Epim Ϫ/Ϫ mice (with global Epim deletion) have increased small bowel crypt cell proliferation and crypt fission during weaning, resulting in increased small bowel length (23).…”

Section: Introductionmentioning

confidence: 99%

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Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

Vishy

Swietlicki

Gazit

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Stem cell therapy is a potential therapeutic approach for disorders characterized by intestinal injury or loss of functional surface area. Stem cell function and proliferation are mediated by the stem cell niche. Stromal cells such as intestinal subepithelial myofibroblasts (ISEMFs) are important but poorly studied components of the stem cell niche. To examine the role of ISEMFs, we have previously generated mice with deletion of epimorphin ( Epim), an ISEMF protein and member of the syntaxin family of intracellular vesicle docking proteins that regulate cell secretion. Herein we explore the mechanisms for previous observations that Epim deletion increases gut crypt cell proliferation, crypt fission, and small bowel length in vivo. Stem cell-derived crypt culture techniques were used to explore the interaction between enteroids and myofibroblasts from Epim and WT mice. Enteroids cocultured with ISEMFS had increased growth and crypt-like budding compared with enteroids cultured without stromal support. Epim deletion in ISEMFs resulted in increased enteroid budding and surface area compared with cocultures with wild-type (WT) ISEMFs. In primary crypt cultures, Epim enteroids had significantly increased surface area and budding compared with WTs. However, stem cell assays comparing the number of Epim vs. WT colony-forming units after first passage showed no differences in the absence of ISEMF support. Epim vs. WT ISEMFs had increased Wnt4 expression, and addition of Wnt4 to WT cocultures enhanced budding. We conclude that ISEMFs play an important role in the stem cell niche. Epim regulates stem cell proliferation and differentiation via stromal contributions to the niche microenvironment. NEW & NOTEWORTHY The role of subepithelial intestinal myofibroblasts (ISEMFs) in the gut stem cell niche is controversial. We provide novel evidence supporting ISEMFs as important niche contributors. We show that the in vivo intestinal effects of deletion of myofibroblast Epim can be recapitulated in crypt stem cell cultures in vitro. ISEMFs support cocultured stem cell proliferation and enteroid growth, and these effects are augmented by deletion of Epim, a syntaxin that regulates myofibroblast cell secretion.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Coculture Of Isemfs With Enteroids Increases Enteroid Growthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

Vishy

Swietlicki

Gazit

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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SNARE proteins: Core engines of membrane fusion in cancer

Liu,

Dang,

Zhang

et al. 2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Mesenchymal Cells in Colon Cancer

et al. 2017

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Mesenchymal cells in the intestine comprise a variety of cell types of diverse origins, functions, and molecular markers. They provide mechanical and structural support and have important functions during intestinal organogenesis, morphogenesis, and homeostasis. Recent studies of the human transcriptome have revealed their importance in the development of colorectal cancer, and studies from animal models have provided evidence for their roles in the pathogenesis of colitis-associated cancer and sporadic colorectal cancer. Mesenchymal cells in tumors, called cancer-associated fibroblasts, arise via activation of resident mesenchymal cell populations and the recruitment of bone marrow-derived mesenchymal stem cells and fibrocytes. Cancer-associated fibroblasts have a variety of activities that promote colon tumor development and progression; these include regulation of intestinal inflammation, epithelial proliferation, stem cell maintenance, angiogenesis, extracellular matrix remodeling, and metastasis. We review the intestinal mesenchymal cell-specific pathways that regulate these processes, with a focus on their roles in mediating interactions between inflammation and carcinogenesis. We also discuss how increasing our understanding of intestinal mesenchymal cell biology and function could lead to new strategies to identify and treat colitis-associated cancers.

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Epimorphin deletion inhibits polyposis in theApc^min/+mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion

Cited by 6 publications

References 38 publications

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

SNARE proteins: Core engines of membrane fusion in cancer

Mesenchymal Cells in Colon Cancer

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