(534f) Quantitative Model Analysis with Qualitative Biological Data: Stem Cell Autoregulation Mechanisms In the Drosophila Germarium

Complex organisms maintain stable populations of stem cells to maintain health and support somatic tissues.  In the germline stem cells (GSC) of the Drosophila ovary, Bone Morphogenetic Protein (BMP) signaling regulates the decision between stem cell self renewal or differentiation.  Key players have been elucidated in the intracellular network that regulates the response to BMPs, however the interaction between intra- and extracellular regulation of BMP signaling remains unknown.  Multiple hypotheses on regulatory mechanisms are indistinguishable based on current qualitative comparisons to data.  The data available for the germarium are insufficient to optimize model fitness due to a lack of quantitative value in the fluorescent expression and immunohistochemical images.  We designed a method to quantitatively constrain the models with existing data, employing multiobjective optimization and optimal scaling of qualitative data.  To investigate whether the proposed system is sufficient to autoregulate population, we have developed two mathematical models, considering both intra- and extracellular interactions: a local model for a single cell receiving BMP signaling and a spatial extracellular model of the germarium.  We converted the qualitative observation-based data into constraints on a quantitative representation and measured model-data correspondence with an optimal scaling least-squares method.  Regulation of a small number of stem cells and the replenishment of an empty niche are investigated by simulation on the spatial model.  Autoregulation is reproduced by combining intra- and extracellular regulation in the spatial multi-cell model with a hypothetical mechanism of cell-mediated competition for limiting amounts of ligand.