Retrograde movements determine effective stem cell numbers in the intestine
Azkanaz M, Corominas-Murtra B, Ellenbroek SIJ, Bruens L, Webb AT, Laskaris D, Oost KC, Lafirenze SJA, Annusver K, Messal HA, Iqbal S, Flanagan DJ, Huels DJ, Rojas-Rodríguez F, Vizoso M, Kasper M, Sansom OJ, Snippert HJ, Liberali P, Simons BD, Katajisto P, Hannezo EB, van Rheenen J. 2022. Retrograde movements determine effective stem cell numbers in the intestine. Nature. 607(7919), 548–554.
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Author
Azkanaz, Maria;
Corominas-Murtra, BernatISTA 
;
Ellenbroek, Saskia I. J.;
Bruens, Lotte;
Webb, Anna T.;
Laskaris, Dimitrios;
Oost, Koen C.;
Lafirenze, Simona J. A.;
Annusver, Karl;
Messal, Hendrik A.;
Iqbal, Sharif;
Flanagan, Dustin J.
All
;
Ellenbroek, Saskia I. J.;
Bruens, Lotte;
Webb, Anna T.;
Laskaris, Dimitrios;
Oost, Koen C.;
Lafirenze, Simona J. A.;
Annusver, Karl;
Messal, Hendrik A.;
Iqbal, Sharif;
Flanagan, Dustin J.
All
Corresponding author has ISTA affiliation
Department
Abstract
The morphology and functionality of the epithelial lining differ along the intestinal tract, but tissue renewal at all sites is driven by stem cells at the base of crypts1,2,3. Whether stem cell numbers and behaviour vary at different sites is unknown. Here we show using intravital microscopy that, despite similarities in the number and distribution of proliferative cells with an Lgr5 signature in mice, small intestinal crypts contain twice as many effective stem cells as large intestinal crypts. We find that, although passively displaced by a conveyor-belt-like upward movement, small intestinal cells positioned away from the crypt base can function as long-term effective stem cells owing to Wnt-dependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the large intestine restricts cell repositioning, leading to a reduction in effective stem cell number. Moreover, after suppression of the retrograde movement in the small intestine, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that the number of effective stem cells is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated.
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Publishing Year
Date Published
2022-07-13
Journal Title
Nature
Publisher
Springer Nature
Acknowledgement
We thank the members of the van Rheenen laboratory for reading the manuscript, and the members of the bioimaging, FACS and animal facility of the NKI for experimental support. We acknowledge the staff at the MedH Flow Cytometry core facility, Karolinska Institutet, and LCI facility/Nikon Center of Excellence, Karolinska Institutet. This work was financially supported by the Netherlands Organization of Scientific Research NWO (Veni grant 863.15.011 to S.I.J.E. and Vici grant 09150182110004 to J.v.R.) and the CancerGenomics.nl (Netherlands Organisation for Scientific Research) program (to J.v.R.) the Doctor Josef Steiner Foundation (to J.v.R). B.D.S. acknowledges funding from the Royal Society E.P. Abraham Research Professorship (RP\R1\180165) and the Wellcome Trust (098357/Z/12/Z and 219478/Z/19/Z). B.C.-M. acknowledges the support of the field of excellence ‘Complexity of life in basic research and innovation’ of the University of Graz. O.J.S. and their laboratory acknowledge CRUK core funding to the CRUK Beatson Institute (A17196 and A31287) and CRUK core funding to the Sansom laboratory (A21139). P.K. and their laboratory are supported by grants from the Swedish Research Council (2018-03078), Cancerfonden (190634), Academy of Finland Centre of Excellence (266869, 304591 and 320185) and the Jane and Aatos Erkko Foundation. P.L. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 758617). E.H. acknowledges funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 851288).
Volume
607
Issue
7919
Page
548-554
ISSN
eISSN
IST-REx-ID
Cite this
Azkanaz M, Corominas-Murtra B, Ellenbroek SIJ, et al. Retrograde movements determine effective stem cell numbers in the intestine. Nature. 2022;607(7919):548-554. doi:10.1038/s41586-022-04962-0
Azkanaz, M., Corominas-Murtra, B., Ellenbroek, S. I. J., Bruens, L., Webb, A. T., Laskaris, D., … van Rheenen, J. (2022). Retrograde movements determine effective stem cell numbers in the intestine. Nature. Springer Nature. https://doi.org/10.1038/s41586-022-04962-0
Azkanaz, Maria, Bernat Corominas-Murtra, Saskia I. J. Ellenbroek, Lotte Bruens, Anna T. Webb, Dimitrios Laskaris, Koen C. Oost, et al. “Retrograde Movements Determine Effective Stem Cell Numbers in the Intestine.” Nature. Springer Nature, 2022. https://doi.org/10.1038/s41586-022-04962-0.
M. Azkanaz et al., “Retrograde movements determine effective stem cell numbers in the intestine,” Nature, vol. 607, no. 7919. Springer Nature, pp. 548–554, 2022.
Azkanaz M, Corominas-Murtra B, Ellenbroek SIJ, Bruens L, Webb AT, Laskaris D, Oost KC, Lafirenze SJA, Annusver K, Messal HA, Iqbal S, Flanagan DJ, Huels DJ, Rojas-Rodríguez F, Vizoso M, Kasper M, Sansom OJ, Snippert HJ, Liberali P, Simons BD, Katajisto P, Hannezo EB, van Rheenen J. 2022. Retrograde movements determine effective stem cell numbers in the intestine. Nature. 607(7919), 548–554.
Azkanaz, Maria, et al. “Retrograde Movements Determine Effective Stem Cell Numbers in the Intestine.” Nature, vol. 607, no. 7919, Springer Nature, 2022, pp. 548–54, doi:10.1038/s41586-022-04962-0.
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