The adult ovary at single cell resolution: an expert review

The ovaries play a crucial role in both the endocrine health and fertility of adult women. The fundamental functional units of the ovaries, primordial follicles, form during fetal development and constitute the ovarian reserve. Ovaries age prematurely in comparison to other organs, with the quality of oocytes declining steeply prior to the entire reserve becoming depleted, usually around age 50. Despite the pivotal role of ovaries in women's overall health, surprisingly little is known about the mechanisms controlling follicle dormancy, growth activation, atresia, maturation, and oocyte quality. Understanding ovarian function on a cellular and molecular level is increasingly important for several reasons. First, the global trend of women delaying childbirth creates a growing population of patients wishing to conceive when the quality and quantity of their oocytes are already critically low. Second, conditions affecting the ovaries, such as polycystic ovary syndrome and endometriosis, are widespread, yet diagnosis and treatment still present challenges. Lastly, advancements in cancer therapies have increased the number of cancer survivors who contend with late complications affecting fertility and hormonal balance. Clearly, a better understanding of diseases, aging, and toxicity in ovaries is needed for the development of novel treatments, preventive therapies, and safer pharmaceuticals. Human ovaries are notoriously difficult to obtain for research due to their pivotal role in women's health, and the highly heterogeneous distribution of follicles within the tissue combined with monthly cyclical changes present further challenges. Single-cell profiling techniques are creating new opportunities, enabling the characterization of small amounts of tissue with unprecedented resolution. Here, we review the literature on single-cell characterization of adult, reproductive-age ovaries. The majority of the 46 identified studies have focused on oocytes discarded during assisted reproduction, with only a handful focusing on ovarian tissue. The overwhelming focus of the studies is on follicles and oocytes, although the somatic cell niche in the ovary undoubtedly plays an important role in endocrine function and follicle biology. Altogether, the studies reveal unexpected diversity and heterogeneity among ovarian somatic and germ cells, highlighting the prevailing knowledge gaps in basic ovarian biology. As the most common outcome for a follicle is atresia, it is possible that part of the cell diversity relates to the biology of follicles destined to degenerate. The absence of spatial coordinates in single-cell studies further complicates the interpretation of the roles and significance of the various reported cell clusters. Accomplishing a representative ovarian single-cell atlas will require merging these studies. However, direct comparisons are challenging due to nonuniform nomenclature, differing tissue sources, varying meta-data reporting, and lack of gold standards in technical approaches. Although these reports establish a single-cell draft of adult-fertile age human ovaries, more detailed metadata and better quality reporting will be essential for the development of a robust ovarian cell atlas in health and disease.