Retrograde movements determine effective stem cell numbers in the intestine

Maria Azkanaz, Bernat Corominas-Murtra, Saskia I. J. Ellenbroek, Lotte Bruens, Anna T. Webb, Dimitrios Laskaris, Koen C. Oost, Simona J. A. Lafirenze, Karl Annusver, Hendrik A. Messal, Sharif Iqbal, Dustin J. Flanagan, David J. Huels, Felipe Rojas-Rodríguez, Miguel Vizoso, Maria Kasper, Owen J. Sansom, Hugo J. Snippert, Prisca Liberali, Benjamin D. Simons (), Pekka Katajisto (), Edouard Hannezo () and Jacco van Rheenen ()
Additional contact information
Maria Azkanaz: The Netherlands Cancer Institute
Bernat Corominas-Murtra: University of Graz
Saskia I. J. Ellenbroek: The Netherlands Cancer Institute
Lotte Bruens: The Netherlands Cancer Institute
Anna T. Webb: Karolinska Institutet
Dimitrios Laskaris: The Netherlands Cancer Institute
Koen C. Oost: Friedrich Miescher Institute for Biomedical Research (FMI)
Simona J. A. Lafirenze: The Netherlands Cancer Institute
Karl Annusver: Karolinska Institutet
Hendrik A. Messal: The Netherlands Cancer Institute
Sharif Iqbal: University of Helsinki
Dustin J. Flanagan: CRUK Beatson Institute
David J. Huels: Oncode Institute
Felipe Rojas-Rodríguez: The Netherlands Cancer Institute
Miguel Vizoso: The Netherlands Cancer Institute
Maria Kasper: Karolinska Institutet
Owen J. Sansom: CRUK Beatson Institute
Hugo J. Snippert: Oncode Institute
Prisca Liberali: Friedrich Miescher Institute for Biomedical Research (FMI)
Benjamin D. Simons: University of Cambridge
Pekka Katajisto: Karolinska Institutet
Edouard Hannezo: Institute for Science and Technology Austria
Jacco van Rheenen: The Netherlands Cancer Institute

Nature, 2022, vol. 607, issue 7919, 548-554

Abstract: 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 crypts1–3. 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.

Date: 2022
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DOI: 10.1038/s41586-022-04962-0

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