title: Emergent stem cell homeostasis in the C. elegans germline is revealed by hybrid modeling.
abstract: The establishment of homeostasis among cell growth, differentiation, and apoptosis is of key importance for organogenesis. Stem cells respond to temporally and spatially regulated signals by switching from mitotic proliferation to asymmetric cell division and differentiation. Executable computer models of signaling pathways can accurately reproduce a wide range of biological phenomena by reducing detailed chemical kinetics to a discrete, finite form. Moreover, coordinated cell movements and physical cell-cell interactions are required for the formation of three-dimensional structures that are the building blocks of organs. To capture all these aspects, we have developed a hybrid executable/physical model describing stem cell proliferation, differentiation, and homeostasis in the Caenorhabditis elegans germline. Using this hybrid model, we are able to track cell lineages and dynamic cell movements during germ cell differentiation. We further show how apoptosis regulates germ cell homeostasis in the gonad, and propose a role for intercellular pressure in developmental control. Finally, we use the model to demonstrate how an executable model can be developed from the hybrid system, identifying a mechanism that ensures invariance in fate patterns in the presence of instability.
authors.affiliation: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom; Microsoft Research Cambridge, Cambridge, UK. Electronic address: bh418@mrc-cu.cam.ac.uk.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hall
authors.affiliation: Department of Computer Science, University of Leicester, Leicester, UK.
authors.forename: Nir
authors.initials: N
authors.lastname: Piterman
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Hajnal
authors.affiliation: Microsoft Research Cambridge, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge, UK. Electronic address: jasmin.fisher@microsoft.com.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D017173:Caenorhabditis elegans / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D005854:Germ Cells / Q000502:physiology*; D006066:Gonads / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D008954:Models, Biological; D013234:Stem Cells / Q000502:physiology*; D014741:Video Recording