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.
