Recent research in mice and humans have discovered a stem cell population in ovaries that can form eggs. However, this discovery begs a question: namely, why do adult female mammals run out of eggs in their lifetime if they have a stem cell population that can produce eggs?
New research from the Carnegie Institute for Science demonstrates that adult mice do not use stem to produce new eggs, thus answering this apparent conundrum.
Before birth, mouse and human ovaries contain an abundant supply of germ cells that originate from primordial germ cells that form from the inner layer of the primary umbilical vesicle (otherwise known as the yolk sac). Between the time when the embryo is four to six weeks old, the primordial germ cells (PGCs) migrate from the wall of the primary umbilical vesicle to the gut tube. From the gut tube, the PGCs migrate to the dorsal body wall by means of the mesentery that suspends the gut from the body wall. Once in the body wall, the PGCs come to rest on either side of the midline in the loose mesenchymal tissue just inside the membranous lining of the body cavity (known more technically as the coelomic cavity).
Most of the PGCs populate the region of the body wall at the level that will form the gonads. During their migration, PGCs continue to multiply by means of mitosis, which increase their numbers substantially. Some PGCs may become stranded during their migration, coming to rest at extragonadal sites. Occasionally, stray germ cells of this type may give rise to a type of tumor called a teratoma.
Once in their final location, the PGCs will stimulate the formation of the genital or gonadal ridge.
In females, PGCs (which are now called gonocytes) undergo a few more mitotic divisions after they are surrounded by the somatic support cells and become intimately associated with them. The gonocytes differentiate into oogonia, and by the 5th month of fetal development all oogonia initiate meiosis. After they initiate meiosis, the oogonia are called primary oocytes. However, during an early phase of meiosis all sex cells enter a state of dormancy, and they remain in meiotic arrest as primary oocytes until sexual maturity. Beginning at puberty, each month a few ovarian follicles resume development in response to the monthly surge of pituitary gonadotropic hormones, but usually only one primary oocyte matures into a secondary oocyte and is ovulated. This oocyte enters a second phase of meiotic arrest and does not actually complete meiosis unless it is fertilized. These monthly cycles continue until the onset of menopause at approximately 50 years of age.
Near the time of birth, the ovaries of mice and humans contain an abundant supply of eggs that will be released from follicles during ovulation each menstrual cycle. At the birth of the baby, she will possess a large reserve of primordial follicles that contain a single egg surrounded by supporting follicle cells. Evidence of new follicle production is absent after birth. Therefore, it has long been thought that the supply of follicles is fixed at birth and eventually is exhausted at menopause.
During the last decade, researchers have found primordial follicles in adult mouse ovaries that turn over and claimed that adult germ-line stem cells constantly resupply the follicle pool and sustain ovulation. These claims were based on observations of ovarian tissue and one the behavior of extremely rare ovarian cells after these cells were cultured for some time in the laboratory. Such criteria are subjective, especially in light of the fact that culturing cells for long periods of time in the laboratory can effectively reprogram them.
At Carnegie, Lei Lei and Allan Spradling used a technique that tracks individual cells and their progeny within living tissue over a specific time course. The cells are marked with a gene, and this gene is inherited by the progeny of that cell, thus allowing the careful tracking of all the progeny of that cell or those cells. This technique is called “lineage tracking” and it is a very popular technique in developmental and cell biology.
By subjecting primordial follicles to lineage tracking, Lei and Spradling showed that germ-line stem cell activity cannot be detected in mice. Furthermore, primordial follicles are stable, and even if half the existing follicles die off, no germ-line stem cell activity is detectable. This research does not prove that there are no germ-line stem cell divisions within the ovary of the mouse, but it does place an upper limit on the divisions of the germ-line stem cell population of one division every two weeks at the most, which is biologically insignificant.
What then can be said about the germ-line stem cell cultures isolated in the laboratory? According to Alan Spradling, the cells “likely arise by dedifferentiation in culture,” and “the same safety and reliability concerns would apply as to any laboratory-generated cell type that lacks a normal counterpart” in the body.
This should be a warning to those conclusions that are solely derived from experiments conducted in culture alone and not in a living creature as well.