PT  - JOURNAL ARTICLE
AU  - Reynolds, Amy
AU  - Wharton, Natalia
AU  - Parris, Alyson
AU  - Mitchell, Esther
AU  - Sobolewski, Anastasia
AU  - Kam, Christy
AU  - Bigwood, Loren
AU  - El Hadi, Ahmed
AU  - Münsterberg, Andrea
AU  - Lewis, Michael
AU  - Speakman, Christopher
AU  - Stebbings, William
AU  - Wharton, Richard
AU  - Sargen, Kevin
AU  - Tighe, Richard
AU  - Jamieson, Crawford
AU  - Hernon, James
AU  - Kapur, Sandeep
AU  - Oue, Naohide
AU  - Yasui, Wataru
AU  - Williams, Mark R
TI  - Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium
AID  - 10.1136/gutjnl-2012-304067
DP  - 2014 Apr 01
TA  - Gut
PG  - 610--621
VI  - 63
IP  - 4
4099  - http://gut.bmj.com/content/63/4/610.short
4100  - http://gut.bmj.com/content/63/4/610.full
SO  - Gut2014 Apr 01; 63
AB  - 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.