Coupled Somatic Cell Kinetics and Germ Cell Growth: Multiscale Model-Based Insight on Ovarian Follicular Development

The development of ovarian follicles is a unique instance of a morphogenesis process still occurring during adult life and resulting from the interactions between somatic and germ cells. In mammals, the initiation of follicular development from the pool of resting follicles is characterized by an increase in the oocyte size concomitant with the surrounding somatic cells proliferating to build an avascular tissue called granulosa. We present a stochastic individual-based model describing the first stages of follicular development, where the cell population is structured with respect to age (progression within the cell cycle) and space (radial distance from the oocyte). The model accounts for the molecular dialogue existing between the oocyte and granulosa cells. Three dynamically interacting scales are considered in the model: (i) a microscopic, local scale corresponding to an individual cell embedded in its immediate environment, (ii) a mesoscopic, semi-local scale corresponding to anatomical or functional areas of follicles and (iii) a macroscopic, global scale corresponding to the morphology of the follicle. Numerical simulations are performed to reproduce the 3D morphogenesis of follicles and follow simultaneously the detailed spatial distribution of individual granulosa cells, their organization as concentric layers or functional cell clones and the increase in the follicle size. Detailed quantitative simulation results are provided in the ovine species, in which well characterized genetic mutations lead to a variety of phenotypic follicle morphogenesis. The model can help to explain pathological situations of imbalance between oocyte growth and follicular cell proliferation