IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1005400.html
   My bibliography  Save this article

The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt

Author

Listed:
  • Sophie K Kay
  • Heather A Harrington
  • Sarah Shepherd
  • Keith Brennan
  • Trevor Dale
  • James M Osborne
  • David J Gavaghan
  • Helen M Byrne

Abstract

The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch’s interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain its neighbours in mitotically active states.Author summary: Epithelial cells which line the intestine form finger-shaped structures called crypts; these undergo a process of renewal at the base, causing cells to migrate upwards until they die and are sloughed off into the gut. Much of our understanding of how crypts function rests upon two processes: proliferation, in which cells divide to produce ‘daughter cells’; and differentiation, in which cells become progressively more specialised as they migrate along the crypt axis and mature. Coordinated proliferation and differentiation enable each crypt to renew itself and to produce a range of specialised cell types essential to its healthy functioning. In this paper we build a mathematical model for two reaction pathways which regulate proliferation and differentiation. We use this model to explore how crosstalk between these pathways in cell pairs influences the generation of distinct cell fates in intestinal tissues. By modifying our model to represent abnormal, ‘mutant’ cells, we investigate abnormalities typical of early colorectal cancer. Computational simulation of our model identifies an important region of crosstalk in our reaction network which determines whether cells adopt the same fate as one another, or different fates. Our model may prove useful for realistic simulations of whole crypts in the future.

Suggested Citation

  • Sophie K Kay & Heather A Harrington & Sarah Shepherd & Keith Brennan & Trevor Dale & James M Osborne & David J Gavaghan & Helen M Byrne, 2017. "The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt," PLOS Computational Biology, Public Library of Science, vol. 13(2), pages 1-28, February.
  • Handle: RePEc:plo:pcbi00:1005400
    DOI: 10.1371/journal.pcbi.1005400
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1005400
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005400&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1005400?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Toshiro Sato & Robert G. Vries & Hugo J. Snippert & Marc van de Wetering & Nick Barker & Daniel E. Stange & Johan H. van Es & Arie Abo & Pekka Kujala & Peter J. Peters & Hans Clevers, 2009. "Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche," Nature, Nature, vol. 459(7244), pages 262-265, May.
    2. Silvia Fre & Mathilde Huyghe & Philippos Mourikis & Sylvie Robine & Daniel Louvard & Spyros Artavanis-Tsakonas, 2005. "Notch signals control the fate of immature progenitor cells in the intestine," Nature, Nature, vol. 435(7044), pages 964-968, June.
    3. Zvia Agur & Oleg U Kirnasovsky & Genadiy Vasserman & Lilach Tencer-Hershkowicz & Yuri Kogan & Hannah Harrison & Rebecca Lamb & Robert B Clarke, 2011. "Dickkopf1 Regulates Fate Decision and Drives Breast Cancer Stem Cells to Differentiation: An Experimentally Supported Mathematical Model," PLOS ONE, Public Library of Science, vol. 6(9), pages 1-10, September.
    4. Johan H. van Es & Marielle E. van Gijn & Orbicia Riccio & Maaike van den Born & Marc Vooijs & Harry Begthel & Miranda Cozijnsen & Sylvie Robine & Doug J. Winton & Freddy Radtke & Hans Clevers, 2005. "Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells," Nature, Nature, vol. 435(7044), pages 959-963, June.
    5. Tannishtha Reya & Hans Clevers, 2005. "Wnt signalling in stem cells and cancer," Nature, Nature, vol. 434(7035), pages 843-850, April.
    6. David Sprinzak & Amit Lakhanpal & Lauren LeBon & Leah A. Santat & Michelle E. Fontes & Graham A. Anderson & Jordi Garcia-Ojalvo & Michael B. Elowitz, 2010. "Cis-interactions between Notch and Delta generate mutually exclusive signalling states," Nature, Nature, vol. 465(7294), pages 86-90, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jong Hoon Won & Jacob S. Choi & Joon-Il Jun, 2022. "CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Jina Yun & Simon Hansen & Otto Morris & David T. Madden & Clare Peters Libeu & Arjun J. Kumar & Cameron Wehrfritz & Aaron H. Nile & Yingnan Zhang & Lijuan Zhou & Yuxin Liang & Zora Modrusan & Michelle, 2023. "Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Yi Liu & Efren Reyes & David Castillo-Azofeifa & Ophir D. Klein & Todd Nystul & Diane L. Barber, 2023. "Intracellular pH dynamics regulates intestinal stem cell lineage specification," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Antonella Fazio & Dora Bordoni & Jan W. P. Kuiper & Saskia Weber-Stiehl & Stephanie T. Stengel & Philipp Arnold & David Ellinghaus & Go Ito & Florian Tran & Berith Messner & Anna Henning & Joana P. Be, 2022. "DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Yang Liu & Qi Chen & Hyun-Woo Jeong & Bong Ihn Koh & Emma C. Watson & Cong Xu & Martin Stehling & Bin Zhou & Ralf H. Adams, 2022. "A specialized bone marrow microenvironment for fetal haematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Tsunaki Higa & Yasutaka Okita & Akinobu Matsumoto & Shogo Nakayama & Takeru Oka & Osamu Sugahara & Daisuke Koga & Shoichiro Takeishi & Hirokazu Nakatsumi & Naoki Hosen & Sylvie Robine & Makoto M. Take, 2022. "Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Suran Kim & Sungjin Min & Yi Sun Choi & Sung-Hyun Jo & Jae Hun Jung & Kyusun Han & Jin Kim & Soohwan An & Yong Woo Ji & Yun-Gon Kim & Seung-Woo Cho, 2022. "Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    8. Clara Morral & Arshad Ayyaz & Hsuan-Cheng Kuo & Mardi Fink & Ioannis I. Verginadis & Andrea R. Daniel & Danielle N. Burner & Lucy M. Driver & Sloane Satow & Stephanie Hasapis & Reem Ghinnagow & Lixia , 2024. "p53 promotes revival stem cells in the regenerating intestine after severe radiation injury," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Mingming Wu & Xiao Zhang & Weijie Zhang & Yi Shiou Chiou & Wenchang Qian & Xiangtian Liu & Min Zhang & Hong Yan & Shilan Li & Tao Li & Xinghua Han & Pengxu Qian & Suling Liu & Yueyin Pan & Peter E. Lo, 2022. "Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Shuting Li & Chia-Wen Lu & Elia C. Diem & Wang Li & Melanie Guderian & Marc Lindenberg & Friederike Kruse & Manuela Buettner & Stefan Floess & Markus R. Winny & Robert Geffers & Hans-Hermann Richnow &, 2022. "Acetyl-CoA-Carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5+ intestinal stem cell function," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    11. Manqiang Lin & Kimberly Hartl & Julian Heuberger & Giulia Beccaceci & Hilmar Berger & Hao Li & Lichao Liu & Stefanie Müllerke & Thomas Conrad & Felix Heymann & Andrew Woehler & Frank Tacke & Nikolaus , 2023. "Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    12. Arafath K. Najumudeen & Sigrid K. Fey & Laura M. Millett & Catriona A. Ford & Kathryn Gilroy & Nuray Gunduz & Rachel A. Ridgway & Eve Anderson & Douglas Strathdee & William Clark & Colin Nixon & Jenni, 2024. "KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    13. Liang Yang & Zifeng Ruan & Xiaobing Lin & Hao Wang & Yanmin Xin & Haite Tang & Zhijuan Hu & Yunhao Zhou & Yi Wu & Junwei Wang & Dajiang Qin & Gang Lu & Kerry M. Loomes & Wai-Yee Chan & Xingguo Liu, 2024. "NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Marco Calafiore & Ya-Yuan Fu & Paola Vinci & Viktor Arnhold & Winston Y. Chang & Suze A. Jansen & Anastasiya Egorova & Shuichiro Takashima & Jason Kuttiyara & Takahiro Ito & Jonathan Serody & Susumu N, 2023. "A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    15. Cezanne Miete & Gonzalo P. Solis & Alexey Koval & Martina Brückner & Vladimir L. Katanaev & Jürgen Behrens & Dominic B. Bernkopf, 2022. "Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Xiaochan Xu & Philip Allan Seymour & Kim Sneppen & Ala Trusina & Anuska la Rosa Egeskov-Madsen & Mette Christine Jørgensen & Mogens Høgh Jensen & Palle Serup, 2023. "Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    17. Anna Urciuolo & Giovanni Giuseppe Giobbe & Yixiao Dong & Federica Michielin & Luca Brandolino & Michael Magnussen & Onelia Gagliano & Giulia Selmin & Valentina Scattolini & Paolo Raffa & Paola Caccin , 2023. "Hydrogel-in-hydrogel live bioprinting for guidance and control of organoids and organotypic cultures," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. Elisa Manieri & Guodong Tie & Ermanno Malagola & Davide Seruggia & Shariq Madha & Adrianna Maglieri & Kun Huang & Yuko Fujiwara & Kevin Zhang & Stuart H. Orkin & Timothy C. Wang & Ruiyang He & Neil Mc, 2023. "Role of PDGFRA+ cells and a CD55+ PDGFRALo fraction in the gastric mesenchymal niche," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    19. Carlos Sebastian & Christina Ferrer & Maria Serra & Jee-Eun Choi & Nadia Ducano & Alessia Mira & Manasvi S. Shah & Sylwia A. Stopka & Andrew J. Perciaccante & Claudio Isella & Daniel Moya-Rull & Maria, 2022. "A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    20. Shizuka Miura & Kenichi Horisawa & Tokuko Iwamori & Satoshi Tsujino & Kazuya Inoue & Satsuki Karasawa & Junpei Yamamoto & Yasuyuki Ohkawa & Sayaka Sekiya & Atsushi Suzuki, 2024. "Hepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pcbi00:1005400. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.