Female fertility comes down to the ovarian follicle, which consists of three basic cell types, including a cell type of mysterious origin. This cell type recently revealed its secrets, giving scientists a better understanding of the intertwining cell lineages and communication pathways that are needed to generate a mature egg. With their newfound insights, scientists hope to advance research into ovarian disorders that can result in hormone imbalances and infertility in women.

Of the ovarian follicle’s cell types—the oocyte and the surrounding granulosa cells and theca cells—the theca cells have been the most reticent. Whereas the oocyte and the granulosa cells were of known origin, scientists did not know where theca cells came from or what directed their development.

The answer to this question remained unanswered for decades, but using a technique called lineage tracing, scientists at the National Institute of Environmental Health Sciences (NIEHS) determined that theca cells in mice come from both inside and outside the ovary, from embryonic tissue called mesenchyme.

This finding was reported April 28 in the journal Nature Communications, in an article entitled, “Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells.” According to this article, the theca cell progenitors—Wt1+ cells indigenous to the ovary and Gli1+ mesenchymal cells that migrate from the mesonephros—acquire the theca lineage marker Gli1 in response to paracrine signals that emanate from granulosa cells.

“We don't know why theca cells have two sources, but it tells us something important—a single cell type may actually be made up of different groups of cells,” said NIEHS researcher and corresponding author Humphrey Yao, Ph.D. Without theca cells, Dr. Yao continued, women are unable to produce the hormones that sustain follicle growth.

“Ovaries lacking Dhh/Ihh [Desert hedgehog and Indian hedgehog signals from granulosa cells] exhibit theca layer loss, blunted steroid production, arrested folliculogenesis and failure to form corpora lutea,” the authors of the Nature Communications article reported. “Production of Dhh/Ihh in granulosa cells requires growth differentiation factor 9 (GDF9) from the oocyte.”

The authors concluded that the multicellular interaction that they identified was critical for the formation of a functional theta. Theta cells produce androgen, which is widely thought of as a male hormone. But, in a superb example of teamwork, the granulosa fells convert the androgen to estrogen.

According to Dr. Yao and his colleagues, the molecular signaling system uncovered in the current study is what enables theca cells to make androgen. The crosstalk between the egg, granulosa cells, and theca cells was an unexpected finding, but one that may provide insight into how ovarian disorders arise.

“The problem starts within the theca cell compartment,” said Chang Liu, Ph.D., a visiting fellow in Dr. Yao's group and first author on the paper. “Now that we know what makes these cells grow, we can search for possible genetic mutations or environmental factors that affect the process leading to ovarian cell disorders.”

For future work, Dr. Yao wants to explore the two types of cells that make up theca cells. Since the research has been carried out in mice, Yao will have to determine if the same holds true for humans, but the research may potentially uncover several roles theca cells play in female fertility.