Adult tissue homeostasis appears as a complex process involving multiple agents and scales, its understanding requires an integrative and synthetic view. We propose that adult tissue homeostasis is a spatially organized ecological/social like system determined by a few primitive determinants. The basement of our analysis is that a two-compartment scheme can be used: a stromal compartment hosting mesenchymal stem/stroma cells (MSC) which regulates a functional compartment made of tissue specific differentiated cells. According to their stromal and regenerative role, the clinical uses of MSC are largely investigated now (website: http://clinicaltrials.gov/). The interactions between both compartments are mandatory for tissue homeostasis. Another key determinant is the metabolism that determines, and is influenced by the physiological status and the fate of the cell3. In this context, blood perfusion provides nutrients, O2 and circulating signals. Innervation that is mostly parallel to arterial vessels is essential to control adult immature cell populations and regeneration processes 5. On the other hand, venous vascularization also drains metabolites including CO2 and signals again: this defines different types of niches, gradients and cell activity. However, the extracellular matrix (ECM) and ECM generating cells (mainly myofibroblasts) generate a framework that plays a major role. It serves as cell mechanical anchorage and generates mechanical constraints. It also contributes to migration and plays a cell guidance role. Because the molecular pathways, which govern such primitive determinants, are highly redundant and lead to an overwhelming complexity, we propose an alternative integrative and functional view breaking with conventional approaches.
Our objective is to provide experimental and modelling support to our view of tissue homeostasis as an ecological or social system consisting of two inter-related ‘differentiated’ and ‘stromal’ cell compartments controlled by a limited number of key determinants. We will use adipos tissue as a biological model to establish a proof of concept and apply it to regenerative medicine. Our modelling methodology relies on i) model-data coupling, ii) heuristic based behavioural models. Their combined use in biological modelling constitutes a major step forward. To this aim, a synergetic effort between tissue physiologists, applied mathematicians and physicists will be engaged in this project based on the coupling of the data to heuristic based behavioural models. This project will serve as the basement of this more ambitious project. With this grant, we propose to initiate this framework and to model the structure with few adipose lobules integrating the different determinants in steady-state (control animal) and after diet induced obesity and lipectomy mimicking regeneration processes.