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    The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis.

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    16
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    Author
    Du, H; Nie, Q; Holmes, WR
    Date
    2015-08
    Source Title
    PLoS Computational Biology
    Publisher
    Public Library of Science (PLoS)
    University of Melbourne Author/s
    HOLMES, WILLIAM
    Affiliation
    School of Mathematics and Statistics
    Metadata
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    Document Type
    Journal Article
    Citations
    Du, H., Nie, Q. & Holmes, W. R. (2015). The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis.. PLoS Comput Biol, 11 (8), pp.e1004285-. https://doi.org/10.1371/journal.pcbi.1004285.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255786
    DOI
    10.1371/journal.pcbi.1004285
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543550
    Abstract
    The epithelium of the small intestinal crypt, which has a vital role in protecting the underlying tissue from the harsh intestinal environment, is completely renewed every 4-5 days by a small pool of stem cells at the base of each crypt. How is this renewal controlled and homeostasis maintained, particularly given the rapid nature of this process? Here, based on the recent observations from in vitro "mini gut" studies, we use a hybrid stochastic model of the crypt to investigate how exogenous niche signaling (from Wnt and BMP) combines with auto-regulation to promote homeostasis. This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals. Results show that Paneth cell derived Wnt signals, which have been observed experimentally to sustain crypts in cultured organs, have a dramatically different influence on niche dynamics than does mesenchyme derived Wnt. While this signaling can indeed act as a redundant backup to the exogenous gradient, it introduces a positive feedback that destabilizes the niche and causes its uncontrolled expansion. We find that in this setting, BMP has a critical role in constraining this expansion, consistent with observations that its removal leads to crypt fission. Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure. Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.

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