title: Short-range growth inhibitory signals from the epithelium can drive non-stereotypic branching in the pancreas.
abstract: Many organs such as the vasculature, kidney, lungs, pancreas and several other glands form ramified networks of tubes that either maximize exchange surfaces between two compartments or minimize the volume of an organ dedicated to the production and local delivery of a cell-derived product. The structure of these tubular networks can be stereotyped, as in the lungs, or stochastic with large variations between individuals, as in the pancreas. The principles driving stereotyped branching have attracted much attention and several models have been proposed and refined. Here we focus on the pancreas, as a model of non-stereotyped branching. In many ramified tubular organs, an important role of the mesenchyme as a source of branching signals has been proposed, including in the pancreas. However, our previous work has shown that in the absence of mesenchyme, epithelial cells seeded in vitro in Matrigel form heavily branched organoids. Here we experimentally show that pancreatic organoids grow primarily at the tips. Furthermore, in contrast to classical 'depletion of activator' mechanisms, organoids growing in close vicinity seem not to affect each other's growth before they get in contact. We recapitulate these observations in an in silico model of branching assuming a 'local inhibitor' is secreted by the epithelium. Remarkably this simple mechanism is sufficient to generate branched organoids similar to those observed in vitro, including their transition from filled spheres to a tree like structure. Quantifying the similarity between in silico and in vitro development through a normalized surface to volume ratio, our in silico model predicts that inhibition is likely to be cooperative and that the diffusing inhibitor decays within a length scale of 10-20 μm.
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200 Copenhagen N, Denmark. Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Svend Bertel
authors.initials: SB
authors.lastname: Dahl-Jensen
authors.forename: Manuel
authors.initials: M
authors.lastname: Figueiredo-Larsen
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
authors.forename: Kim
authors.initials: K
authors.lastname: Sneppen
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000502:physiology*; D004848:Epithelium / Q000502:physiology; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D010179:Pancreas / Q000254:growth & development*; D015398:Signal Transduction
chemical_list: D006131:Growth Inhibitors