Dynamics and control of female germ cell populations: understanding aging through population dynamics models – OVOPAUSE

Female reproductive function is supported by a massive production of specialised germ cells, the oocytes. In women, as in most mammals, the stock of oocytes is established in the peri-natal period and it keeps decreasing all along life, leading to its exhaustion at menopause and to reproductive function arrest. Oocytes are surrounded by layers of somatic granulosa cells to form ovarian follicles. Different populations of follicles co-exist in the ovaries: the quiescent primordial follicles, which constitute the stock of follicles, and growing follicles. Regularly and until exhaustion, primordial follicles are recruited in the growing follicle pool, according to tightly regulated dynamics leading to either their final maturation for ovulation or to their elimination by a physiological process. Ovulation requires a tight coordination between the recruitment of an adequate number of primordial follicles and of growing follicles achieving maturation at ovulation. Accelerated exhaustion of follicles is a cause of premature ovarian failure, and disrupted growth also leads to fertility disorders. Controlling primordial and growing follicle population distribution, through the recruitment and subsequent maturation of follicles is a critical issue for fertility, which is at the heart of assisted reproductive technologies.
In this context, the objectives of OVOPAUSE are 1/ to investigate to which extent primordial follicles and growing follicles establish a tight dialogue notably through endocrine/paracrine factors to ensure regular ovulations throughout reproductive life, 2/ to quantify the dynamics and nonlinear interactions at play within the follicle population and 3/ to monitor the depletion of the stock of oocytes over ageing, both before puberty and during reproductive life.
Using innovative imaging approaches and artificial intelligence-based analyses, the distribution of the follicle population will be acquired in young and adult mice and medaka, two relevant animal models for reproductive biology. Experimental manipulations of these models offer the possibility of addressing these issues in both a physiological situation and in a situation where the inter-follicular dialogue is disrupted.
Using population dynamics models, we will build a comprehensive modelling framework to formulate and investigate the control of follicle dynamics. We intend to faithfully reproduce follicle size and maturation distribution, quantitatively and dynamically. Statistical estimation procedures will unveil the controls behind the observed population of oocytes through ageing. A comprehensive parameter sensitivity study will shed light on potential action levers to lengthen the lifespan of the ovarian reserve. We will study in particular scenarios of preservation of the stock of ovarian follicles, which is of crucial importance in oncofertility, or of the over-representation of growing follicles, which is frequently encountered in the polycystic ovary syndrome.