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DEsigning new Paths in The differentiation Hyperspace

Final Report Summary - DEPTH (DEsigning new Paths in The differentiation Hyperspace)

-The muscle is a relatively stable tissue during the life-time of an organism. However, efficient tissue regeneration is activated whenever the muscle experiences a stress caused, for instance, by exercise or by mechanical insults. After injury, or other physiological and pathological perturbations, circulating cells migrate to the muscle and exchange signals with resident progenitor cells to modulate their differentiation programs. Eventually this complex crosstalk yields new muscle fibers. Protracted regeneration, triggered by chronic stress such as for instance in dystrophic patients or during aging, results in a perturbation of this complex orchestrated process.
Understanding the interplay between the extracellular cues and the intracellular signaling
mechanisms that redirect cell differentiation programs is a daunting but essential task. Several
qualitative and quantitative observations relating to both intercellular and intracellular signaling mechanisms in the muscle have been reported in the literature. What is missing is an integration of these observations into a holistic and structured picture that can be incorporated into a quantitative and predictive model.
Our project aimed at building such a model. The approach is based on the integration of experimental analysis and computational modeling. We have assembled a simple dynamic model that explains the most solid experimental observations. We are now in the process of building complexity on this in order to be able to explain most of the experimental observations. The initial model prototype has guided the design of new experiments to extract quantitative parameters to be integrated into the model.
The experimental system aims at reproducing ex vivo, in a Petri dish, the main characteristics of the in vivo regeneration process. This was achieved by combining satellite cells, fibro adipogenic precursors and macrophages. These different primary cell types when cultivated together exchange signals and eventually contribute to assemble new functional (contracting) muscle myofibers. This complex process is analyzed by mass cytometry, a powerful technology that allows dissecting the differentiation process at the single cell level. The results of these experiments guide the optimization of the initial model based on prior knowledge. The end goal of the project is a multilevel (intracellular signaling, cell cell interaction, tissue topology) three-dimensional model of the muscle regeneration process. This approach is aided by the identification of small molecules that perturb the process and that, at the same time, offer a toolbox for controlling the different steps of the differentiation process, Eventually this may enable us to rationally control the regeneration process
in physiological and pathological conditions.