RT Journal Article
SR Electronic
T1 Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 610
OP 621
DO 10.1136/gutjnl-2012-304067
VO 63
IS 4
A1 Reynolds, Amy
A1 Wharton, Natalia
A1 Parris, Alyson
A1 Mitchell, Esther
A1 Sobolewski, Anastasia
A1 Kam, Christy
A1 Bigwood, Loren
A1 El Hadi, Ahmed
A1 Münsterberg, Andrea
A1 Lewis, Michael
A1 Speakman, Christopher
A1 Stebbings, William
A1 Wharton, Richard
A1 Sargen, Kevin
A1 Tighe, Richard
A1 Jamieson, Crawford
A1 Hernon, James
A1 Kapur, Sandeep
A1 Oue, Naohide
A1 Yasui, Wataru
A1 Williams, Mark R
YR 2014
UL http://gut.bmj.com/content/63/4/610.abstract
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.