Intestinal Epithelial-Specific mTORC1 Activation Enhances Intestinal Adaptation After Small Bowel Resection
| Autor: | Bola Aladegbami, Brad W. Warner, Jun Guo, Lauren Barron, Raphael C. Sun, Christopher R. Erwin |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
WT wild type Pathology medicine.medical_specialty Enterocyte SBR small bowel resection Crypt p-HH3 phosphorylated histone H3 Enteroendocrine cell mTOR mammalian target of rapamycin Biology digestive system 03 medical and health sciences PCR polymerase chain reaction medicine lcsh:RC799-869 mTORC mammalian target of rapamycin complex PI3K/AKT/mTOR pathway Original Research EGF epidermal growth factor Goblet cell Hepatology S6K S6 kinase i-TSC-/- intestinal epithelial cell–specific tuberous sclerosis complex 1 null mice Gastroenterology Intestinal epithelium Small intestine TSC1 Raptor MMP matrix metalloproteinase 030104 developmental biology medicine.anatomical_structure Differentiation Paneth cell Cancer research lcsh:Diseases of the digestive system. Gastroenterology biological phenomena cell phenomena and immunity TSC tuberous sclerosis complex IHC immunohistochemistry TAM tamoxifen |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 3, Iss 2, Pp 231-244 (2017) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims Intestinal adaptation is a compensatory response to the massive loss of small intestine after surgical resection. We investigated the role of intestinal epithelial cell–specific mammalian target of rapamycin complex 1 (i-mTORC1) in intestinal adaptation after massive small bowel resection (SBR). Methods We performed 50% proximal SBR on mice to study adaptation. To manipulate i-mTORC1 activity, Villin-CreER transgenic mice were crossed with tuberous sclerosis complex (TSC)1flox/flox or Raptorflox/flox mice to inducibly activate or inactivate i-mTORC1 activity with tamoxifen. Western blot was used to confirm the activity of mTORC1. Crypt depth and villus height were measured to score adaptation. Immunohistochemistry was used to investigate differentiation and rates of crypt proliferation. Results After SBR, mice treated with systemic rapamycin showed diminished structural adaptation, blunted crypt cell proliferation, and significant body weight loss. Activating i-mTORC1 via TSC1 deletion induced larger hyperproliferative crypts and disorganized Paneth cells without a significant change in villus height. After SBR, ablating TSC1 in intestinal epithelium induced a robust villus growth with much stronger crypt cell proliferation, but similar body weight recovery. Acute inactivation of i-mTORC1 through deletion of Raptor did not change crypt cell proliferation or mucosa structure, but significantly reduced lysozyme/matrix metalloproteinase-7–positive Paneth cell and goblet cell numbers, with increased enteroendocrine cells. Surprisingly, ablation of intestinal epithelial cell–specific Raptor after SBR did not affect adaptation or crypt proliferation, but dramatically reduced body weight recovery after surgery. Conclusions Systemic, but not intestinal-specific, mTORC1 is important for normal adaptation responses to SBR. Although not required, forced enterocyte mTORC1 signaling after resection causes an enhanced adaptive response. Graphical Abstract |
| Databáze: | OpenAIRE |
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