The Autonomy of Follicle Biology: Applying Ovarian Follicle Culture to Model Development, Differentiation and Transformation

As the fundamental endocrine unit of the ovary, follicle differentiation and transformation inform much of female physiology. The emerging field of in vitro follicle growth centers on the optimization of culture systems to support complete oocyte maturation. In particular, the alginate system has been shown to support the development of mature oocytes, from the mouse to the primate. However, little is known about the mechanisms underlying autonomous follicle growth and differentiation in vitro. Thus the studies herein aimed to apply follicle culture to model development, differentiation, and transformation. Indeed, novel models of the ovarian secretome, follicular rupture, luteinization and ovarian rigidity were developed and characterized. Through analysis of the follicular transcriptome, we identified that cartilage oligomeric matrix protein (COMP) is the most upregulated protein throughout follicle growth. Thus, COMP may be applied clinically as a biomarker of follicle maturity. Additionally, we developed a novel in vitro ovulation model. In these studies we showed that hCG induced autonomous follicular rupture in vitro and applied this model to better understand mechanisms underlying mammalian ovulation and contraceptive compounds. Interestingly, we discovered that the polyphenol, EGCG, has significant contraceptive effects both in vitro and in vivo through inhibition of hCG-induced cAMP. Ongoing studies are exploring its potential translation into a non-hormonal emergency contraceptive. Further, we characterized the luteal phenotypes of follicles post-hCG treatment and described the first in vitro model of luteinization in the rodent, nonhuman primate, and human. Finally, we utilized the tunable properties of alginate to model ovarian rigidity in vitro. In this project we generated a candidate list of mechanosensitive genes through microarray analysis of follicles cultured in permissive versus rigid conditions. Using this list of candidate genes, we identified 13 SNPs linking ovarian rigidity and PCOS in a large patient cohort. Taken together, this body of work shows the numerous translational and discovery-based applications of follicle culture. Moreover, it highlights the striking autonomy of the ovarian follicle.