Genome-wide Metabolic Modeling of Human Ovarian Follicle Development

Human ovarian follicle development is a complex process of the female reproductive system. The functional unit of the ovary i.e., follicle, consist of female germ cell, Oocyte, at the center and somatic cells like Granulosa and Theca cells surrounding the oocyte. These different cell types interact with each other through intracellular and intercellular metabolic communication to produce a mature oocyte for fertilization. Development competence of the oocyte that can render a successful pregnancy depends on the accumulation of the required metabolites and other materials (e.g., proteins, transcripts) essential for later stages, such as fertilization and subsequent embryo pre-implantation. Understanding the complex dynamic and bi-directional communication between the oocyte and granulosa cells to achieve a competent oocyte will help us improve the in-vitro maturation of oocyte that has lesser side effects and cost effective compared to in-vitro fertilization because synthetic hormone is not required for hyperstimulation of ovary. Genome-wide metabolic model of the human ovarian follicle was generated by overlaying human single-cell transcriptomic data from different stages of follicle development to the latest genome-scale human metabolic model (Recon3D) using FASTCORE. Analysis of previously published single cell RNA sequencing data revealed that there were 18,741 actively transcribed genes in the oocyte samples and 17,092 actively transcribed genes in granulosa samples at the different stages of follicle development. Using an unsupervised method, we identified five different clusters that were indeed associated with the different follicular stages (i.e., primordial, primary, secondary, antral, and pre-ovulatory) and cell-type (oocyte and granulosa cells). The Follicle metabolic model contains 10,538 reactions, 3,484 metabolites and 2,954 genes that encode enzymes. As expected, the follicle metabolic model included several key follicle metabolic pathways during follicle development in vivo (such as, pyruvate metabolism, steroid metabolism, androgen and estrogen synthesis and metabolism). In summary, we have developed a human follicle metabolic model for the first time that could help to better understand the biology of human ovarian follicle development and thus serve to develop novel treatments for reproductive diseases in the future, such as polycystic ovarian syndrome (PCOS), endometriosis, or improve in vitro maturation culture system.