title: An integrative computational model for intestinal tissue renewal.
abstract: OBJECTIVE
  The luminal surface of the gut is lined with a monolayer of epithelial cells that acts as a nutrient absorptive engine and protective barrier. To maintain its integrity and functionality, the epithelium is renewed every few days. Theoretical models are powerful tools that can be used to test hypotheses concerning the regulation of this renewal process, to investigate how its dysfunction can lead to loss of homeostasis and neoplasia, and to identify potential therapeutic interventions. Here we propose a new multiscale model for crypt dynamics that links phenomena occurring at the subcellular, cellular and tissue levels of organisation.
  
  
  METHODS
  At the subcellular level, deterministic models characterise molecular networks, such as cell-cycle control and Wnt signalling. The output of these models determines the behaviour of each epithelial cell in response to intra-, inter- and extracellular cues. The modular nature of the model enables us to easily modify individual assumptions and analyse their effects on the system as a whole.
  
  
  RESULTS
  We perform virtual microdissection and labelling-index experiments, evaluate the impact of various model extensions, obtain new insight into clonal expansion in the crypt, and compare our predictions with recent mitochondrial DNA mutation data.
  
  
  CONCLUSIONS
  We demonstrate that relaxing the assumption that stem-cell positions are fixed enables clonal expansion and niche succession to occur. We also predict that the presence of extracellular factors near the base of the crypt alone suffices to explain the observed spatial variation in nuclear beta-catenin levels along the crypt axis.
authors.affiliation: School of Mathematical Sciences, University of Nottingham, Nottingham, UK. ingeborg.vanleeuwen@ki.se
authors.forename: I M M
authors.initials: IM
authors.lastname: van Leeuwen
authors.forename: G R
authors.initials: GR
authors.lastname: Mirams
authors.forename: A
authors.initials: A
authors.lastname: Walter
authors.forename: A
authors.initials: A
authors.lastname: Fletcher
authors.forename: P
authors.initials: P
authors.lastname: Murray
authors.forename: J
authors.initials: J
authors.lastname: Osborne
authors.forename: S
authors.initials: S
authors.lastname: Varma
authors.forename: S J
authors.initials: SJ
authors.lastname: Young
authors.forename: J
authors.initials: J
authors.lastname: Cooper
authors.forename: B
authors.initials: B
authors.lastname: Doyle
authors.forename: J
authors.initials: J
authors.lastname: Pitt-Francis
authors.forename: L
authors.initials: L
authors.lastname: Momtahan
authors.forename: P
authors.initials: P
authors.lastname: Pathmanathan
authors.forename: J P
authors.initials: JP
authors.lastname: Whiteley
authors.forename: S J
authors.initials: SJ
authors.lastname: Chapman
authors.forename: D J
authors.initials: DJ
authors.lastname: Gavaghan
authors.forename: O E
authors.initials: OE
authors.lastname: Jensen
authors.forename: J R
authors.initials: JR
authors.lastname: King
authors.forename: P K
authors.initials: PK
authors.lastname: Maini
authors.forename: S L
authors.initials: SL
authors.lastname: Waters
authors.forename: H M
authors.initials: HM
authors.lastname: Byrne
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D003106:Colon / Q000166:cytology* / Q000502:physiology*; D003198:Computer Simulation; D005109:Extracellular Matrix / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000502:physiology*; D008938:Mitosis / Q000502:physiology; D008954:Models, Biological; D009092:Mucous Membrane / Q000166:cytology / Q000502:physiology; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin