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Colon
Original article
Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium
  1. Amy Reynolds1,
  2. Natalia Wharton1,
  3. Alyson Parris1,
  4. Esther Mitchell1,
  5. Anastasia Sobolewski2,
  6. Christy Kam1,
  7. Loren Bigwood1,
  8. Ahmed El Hadi1,
  9. Andrea Münsterberg1,
  10. Michael Lewis3,
  11. Christopher Speakman3,
  12. William Stebbings3,
  13. Richard Wharton3,
  14. Kevin Sargen3,
  15. Richard Tighe4,
  16. Crawford Jamieson4,
  17. James Hernon3,
  18. Sandeep Kapur3,
  19. Naohide Oue5,
  20. Wataru Yasui5,
  21. Mark R Williams1
  1. 1School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk, UK
  2. 2Department of Gut Health and Food Safety, Institute Strategic Programme, Institute of Food Research, Colney, Norwich Research Park, Norwich, Norfolk, UK
  3. 3Department of Surgery, Norfolk and Norwich University Hospitals Trust, Colney Lane, Norwich Research Park, Norwich, Norfolk, UK
  4. 4Department of Gastroenterology, Norfolk and Norwich University Hospitals Trust, Colney Lane, Norwich Research Park, Norwich, Norfolk, UK
  5. 5Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
  1. Correspondence to Dr Mark R Williams, School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR47TJ, UK; m.r.williams{at}uea.ac.uk

Abstract

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.

  • Stem Cells
  • Imaging
  • Epithelial Proliferation
  • Epithelial Differentiation
  • Epithelial Kinetics

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/

https://doi.org/10.1136/gutjnl-2012-304067

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