Ovarian Cellular Signaling and Molecular Pathways Controlling Female Fertility
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Our laboratory investigates the molecular and cellular processes controlling ovarian function in mammals. We focus on the signaling and genomic crosstalk between the hormones and growth factors.
Check out current projects in the Stocco Lab
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Check out current projects in the Stocco Lab
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Novel role of Salt-Inducible Kinases (SIKs) in the Ovary
Novel role of Salt-Inducible Kinases (SIKs) in the Ovary
The production of mature eggs is the most crucial step towards female fertility. Egg maturation requires a close interaction between Follicle-Stimulating Hormone (FSH) and Insulin-like Growth Factors (IGFs). Of these hormones, FSH is the primary drug used to stimulate egg production in patients with ovulatory dysfunctions. However, FSH is not always effective in these patients. To solve this significant clinical problem, we looked for factors that inhibit FSH actions in the ovary. We discovered that SIKs are expressed in human and rodent granulosa cells (see figure on the right) and that SIK inhibition enhances the stimulatory effect of FSH in the ovary. We hypothesize that SIKs are molecular gatekeepers that repress FSH actions and egg maturation. Since SIK activity can be modulated pharmacologically, our findings could provide benefits for novel therapies to treat ovulatory defects in humans. For instance, SIK-controlled mechanisms and pathways may be used to develop safer and more effective protocols to induce ovulation in infertile women or innovative methods of contraception. Understanding SIKs in ovarian function is a major focus of our current NIH funding.
SIK2 inhibition could be a useful tool in the IVF clinics to assist poor responding patients by increasing their response to FSH.
Novel crosstalk between gonadotropins and growth factors in the ovary
Novel crosstalk between gonadotropins and growth factors in the ovary
We recently described the interaction between FSH and locally produced IGFs on the regulation of granulosa cell (GC) differentiation. Until the publication of our findings, FSH actions were considered to be enough to stimulate the growth of ovarian follicles. Our in vivo and in vitro studies in mouse, rat, and human GCs demonstrated for the first time that the stimulatory effect of FSH in the ovary requires the presence of IGFs. Our discovery revealed that FSH actions are not enough to stimulate ovarian cell proliferation and follicle growth and demonstrate an essential role of the receptor of IGFs in the regulation of survival, proliferation, and differentiation of GCs in vivo. These novel findings represented a paradigm shift in our understanding of how FSH regulates ovarian function. The News and Views editorial called Female Fertility: It Takes Two to Tango (see full text here) reviewed and highlighted the importance of our findings and suggested implications beyond fertility, including ovarian cancer, puberty, and ovarian toxicology. Current funding and research efforts study the signaling crosstalk between FSH and Insulin-like Growth Factors in primary cultures of human ovarian granulosa cells.
Molecular Mechanism Controlling Primary Human Cumulus Cells' Response to Endocrine and Paracrine Factors
Molecular Mechanism Controlling Primary Human Cumulus Cells' Response to Endocrine and Paracrine Factors
The generation of competent oocytes results from a lengthy folliculogenesis process requiring direct and constant communication between the oocyte and the GCs to create the microenvironment necessary for follicle growth. However, it is challenging to study the interaction between the oocyte and the GCs in humans. To overcome this problem, we developed a unique experimental approach that consists of using primary human ovarian cumulus cells obtained from patients undergoing in vitro fertilization (IVF). We validated this approach in several publications establishing that human cumulus cells are an excellent system to study FSH-regulated mechanisms in humans. We also demonstrated that human cumulus cells are targets of oocyte-secreted factors, including growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15). In two recent manuscripts in the Journal of Clinical Endocrinology and Metabolism, we used this experimental approach to demonstrate that only the combination of GDF9 and BMP15 strongly enhances FSH-stimulated estradiol and IGF2 production and that this potentiation involves, at least in part, the IGF system (see figure on the left). The result of this research could be used to improve the in vitro maturation of follicles in humans.
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