Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium
| Autor: | Naohide Oue, Kevin Sargen, Andrea Münsterberg, Christy Kam, Ahmed El Hadi, James Hernon, Christopher Speakman, Mark Williams, William Stebbings, R Tighe, Sandeep Kapur, Natalia Wharton, Wataru Yasui, Amy Reynolds, Anastasia Sobolewski, Richard Wharton, Loren Bigwood, Esther M. Mitchell, Alyson Parris, Crawford Jamieson, Michael P. Lewis |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Colon Cellular differentiation Epithelial Differentiation Crypt Biology Bone morphogenetic protein digestive system Imaging Intestinal mucosa Cell Movement Transforming Growth Factor beta Humans Regeneration Intestinal Mucosa Progenitor cell Wnt Signaling Pathway In Situ Hybridization Aged Cell Proliferation Aged 80 and over Epithelial Proliferation Microscopy Confocal Stem Cells Gastroenterology Wnt signaling pathway LGR5 Cell Differentiation Epithelial Kinetics Middle Aged digestive system diseases Cell biology Bone Morphogenetic Proteins Stem cell Signal Transduction |
| Zdroj: | Gut |
| ISSN: | 1468-3288 0017-5749 |
| DOI: | 10.1136/gutjnl-2012-304067 |
| Popis: | Background A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. Objective To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Design Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Results Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Conclusions Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population. |
| Databáze: | OpenAIRE |
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