Elucidating the role of the hyaluronan matrices on the establishment of ovarian reserve and aging

ABSTRACT In mammals generally, including humans, the ovary ceases its functions little more than halfway through a female's lifespan. This is strikingly different from the changes that occur in other organs, leading to a very long post-reproductive period in humans. Female reproductive aging is characterized by a loss of follicles; follicles

are the functional units of the ovary, consisting of oocytes surrounded by companion granulosa cells. All the oocytes/follicles that the ovary will ever have will have been generated in utero or at a very early postnatal age. The study of ovarian reserve regulation has been very germ cell centric, relegating to a quite secondary role the

ovarian stroma and the microenvironment (including somatic cells and the extracellular matrix). In fact, the microenvironment in which cells grow and develop informs function. Recent publications have shown that the ovarian stroma becomes inflammatory, fibrotic, and stiff with advanced reproductive age. These phenotypes are

mechanistically linked to changes in the hyaluronan (HA) matrix, a ubiquitous and polydisperse extracellular glycosaminoglycan that regulates tissue homeostasis. In its high-molecular-weight (HMW) form, HA binds water and promotes hydration and has anti-inflammatory properties. In contrast, low-molecular-weight (LMW) HA tends

to have pro-inflammatory properties. High levels of HA are associated with stem cell proliferation and protection from differentiation during early embryogenesis. The naked mole-rat (Heterocephalus glaber, NMR) is a unique rodent species which lives up to four decades and maintains reproductive function throughout its entire lifespan.

This extreme longevity is attributable in part to the production of large amounts of very-high-molecular-weight hyaluronan (vHMW-HA). vHMW-HA is produced in NMRs by a uniquely modified version of the hyaluronan synthase 2 gene (Has2). In the proposed research, we will test the overarching hypothesis that the stromal

microenvironment of the fetal ovary, including an HA-rich matrix, regulates the establishment and maintenance of the ovarian reserve and reproductive longevity.