Laronda Lab

Our research addresses fundamental regenerative medicine questions through the lens of reproductive biology. The overarching goals of the Laronda Lab are (1) to understand how the ovarian microenvironment maintains and promotes gametogenesis, (2) to develop new regenerative technologies that restore the full cyclical complement of ovarian hormones with or without restoration of fertility, (3) to translate effective therapies that support endocrine function and/or gamete production for patients.

This research bridges foundational science, translational research and clinical practice.

 

Background

The embryonic gonad develops as a protrusion of proliferating cells along the mesonephric duct. Primordial germ cells, that will become the oogonia, female gametes, or spermatogonia, male gametes, migrate into the developing gonad. As the bipotential gonad becomes an ovary, pre-granulosa cells surround proliferating oogonia and eventually pinch off an oocyte to create a primordial follicle. The cohort of primordial follicles is considered the ovarian reserve and it contains the highest number of follicles right before birth (average of ~300,000) and naturally declines with age until a female enters menopause (~1,000).

         Primordial follicles grow approximately 600 times their size as they develop into large antral follicles that will ovulate fertilizable mature eggs after a female has undergone puberty. This process is dependent on the cyclical hormone production of the pituitary in response to signals from the hypothalamus and triggered by the ovaries. These hormones are necessary for the physiological and psychological transition from childhood to adulthood and maintain systemic homeostasis of systems, such as vascular, metabolic and bone maintenance, throughout a woman’s life. The ovarian environment has to withstand the dynamic changes of folliculogenesis while maintaining a supportive niche for the ovarian reserve.

 

Our research focuses on the oocyte niche by studying the development and differentiation of granulosa and theca cells, the endocrine-responsive and endocrine-producing support cells that surround the female gamete as it progresses to a fertilizable egg. We use primary cells to understand this progression and developed protocols to differentiate granulosa-like cells from human induced pluripotent stem cells. We also study the contribution of the extracellular matrix (ECM) to maintain and regulate ovarian function. We understand that the ECM composition and rigidity around the ovarian reserve differs from that around the growing follicles. We believe these differences contribute, through different mechanotransductive cues, to the ability of the ovary to function as a dynamic organ with cyclical progressions, and alterations in this balance may contribute to disease profiles including premature ovarian failure and hormone insufficiency. We employ methods such as decellularization, and 3D printing to investigate the role of ECM and rigidity on ovarian follicle function. Our goal is to understand the niche that supports oogenesis and maintains ovarian function with the aspiration of creating a bioengineered ovary that will restore or provide fertility and hormone function in patients.