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Colon
Original article
Crypt fusion as a homeostatic mechanism in the human colon
  1. Ann-Marie Baker1,
  2. Calum Gabbutt1,2,
  3. Marc J Williams1,
  4. Biancastella Cereser1,
  5. Noor Jawad1,
  6. Manuel Rodriguez-Justo3,
  7. Marnix Jansen3,
  8. Chris P Barnes2,
  9. Benjamin D Simons4,5,
  10. Stuart AC McDonald1,
  11. Trevor A Graham1,
  12. Nicholas A Wright1
  1. 1 Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
  2. 2 Department of Cell and Developmental Biology, University College London, London, UK
  3. 3 Histopathology, University College London, London, UK
  4. 4 Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
  5. 5 The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK
  1. Correspondence to Professor Trevor A Graham, Barts Cancer Institute, Queen Mary University of London, London, UK; t.graham{at}qmul.ac.uk and Professor Nicholas A Wright, Barts Cancer Institute, Queen Mary University of London, UK; n.a.wright{at}qmul.ac.uk

Abstract

Objective The crypt population in the human intestine is dynamic: crypts can divide to produce two new daughter crypts through a process termed crypt fission, but whether this is balanced by a second process to remove crypts, as recently shown in mouse models, is uncertain. We examined whether crypt fusion (the process of two neighbouring crypts fusing into a single daughter crypt) occurs in the human colon.

Design We used somatic alterations in the gene cytochrome c oxidase (CCO) as lineage tracing markers to assess the clonality of bifurcating colon crypts (n=309 bifurcating crypts from 13 patients). Mathematical modelling was used to determine whether the existence of crypt fusion can explain the experimental data, and how the process of fusion influences the rate of crypt fission.

Results In 55% (21/38) of bifurcating crypts in which clonality could be assessed, we observed perfect segregation of clonal lineages to the respective crypt arms. Mathematical modelling showed that this frequency of perfect segregation could not be explained by fission alone (p<10−20). With the rates of fission and fusion taken to be approximately equal, we then used the distribution of CCO-deficient patch size to estimate the rate of crypt fission, finding a value of around 0.011 divisions/crypt/year.

Conclusions We have provided the evidence that human colonic crypts undergo fusion, a potential homeostatic process to regulate total crypt number. The existence of crypt fusion in the human colon adds a new facet to our understanding of the highly dynamic and plastic phenotype of the colonic epithelium.

  • colon crypt
  • evolutionary dynamics
  • lineage tracing
  • crypt fission
  • crypt fusion
  • mathematical modelling

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/gutjnl-2018-317540

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    Footnotes

    • SACM, TAG and NAW are senior authors.

    • A-MB and CG contributed equally.

    • Contributors A-MB, BC and NJ performed experimental work. CG, CB, BDS and TAG performed mathematical analysis. MR-J, MJ, and NAW performed histological analysis. MR-J, MJ and SACM performed sample identification and collection. A-MB, CG, MW, MJ, BDS, SACM, TAG and NAW analysed data. Figures were compiled by A-MB, CG and MJ. CB, SACM, TAG and NAW designed and supervised the project. A-MB, CG, TAG and NAW wrote the first draft of the manuscript and all authors read and approved the final version.

    • Funding This work was supported by Cancer Research UK (A14895, A-MB and NAW; A19771, TAG), the Wellcome Trust (098357, BDS; 209409/Z/17/Z, CB) and the Medical Research Council (G0901178, BC, NJ and SACM). CG was funded by the BBSRC London Interdisciplinary Biosciences Consortium (LiDo). BDS acknowledges the support of the Royal Society through the provision of the EP Abraham Research Professorship.

    • Competing interests None declared.

    • Ethics approval Normal and IBD colon tissue samples were collected at University College Hospital and St Mark’s Hospital, London, under multicentre ethical approval (07/Q1604/17 and 11/LO/1613). FAP tissue was collected at the Academic Medical Centre, Amsterdam, in accordance with national ethics guidelines on tissue procurement (local protocol 12-543).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This article has been corrected since it published Online First. The senior author statement has been added and the affiliations updated.

    • Patient consent for publication Not required.